PubMed:9603435 JSONTXT

{"project":"NCBI-Disease-Corpus-GPT5-withguidelines","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"DiseaseClass"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":734,"end":754},"obj":"DiseaseClass"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"},{"id":"T7","span":{"begin":1671,"end":1694},"obj":"SpecificDisease"},{"id":"T8","span":{"begin":1909,"end":1925},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-GPT5-noguidelines","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"CompositeMention"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":314,"end":319},"obj":"Modifier"},{"id":"T5","span":{"begin":320,"end":329},"obj":"Modifier"},{"id":"T6","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T7","span":{"begin":381,"end":389},"obj":"Modifier"},{"id":"T8","span":{"begin":391,"end":405},"obj":"Modifier"},{"id":"T9","span":{"begin":411,"end":418},"obj":"Modifier"},{"id":"T10","span":{"begin":420,"end":431},"obj":"Modifier"},{"id":"T11","span":{"begin":714,"end":754},"obj":"CompositeMention"},{"id":"T12","span":{"begin":1455,"end":1468},"obj":"CompositeMention"},{"id":"T13","span":{"begin":1671,"end":1694},"obj":"SpecificDisease"},{"id":"T14","span":{"begin":1909,"end":1925},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-GPT5-guidelineprompt","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"DiseaseClass"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":714,"end":754},"obj":"DiseaseClass"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"},{"id":"T7","span":{"begin":1671,"end":1694},"obj":"SpecificDisease"},{"id":"T8","span":{"begin":1909,"end":1925},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-Moderated1","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"DiseaseClass"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":734,"end":754},"obj":"DiseaseClass"},{"id":"T6","span":{"begin":1455,"end":1468},"obj":"SpecificDisease"},{"id":"T7","span":{"begin":1671,"end":1694},"obj":"DiseaseClass"},{"id":"T8","span":{"begin":1909,"end":1925},"obj":"DiseaseClass"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"sentences","denotations":[{"id":"TextSentencer_T1","span":{"begin":0,"end":154},"obj":"Sentence"},{"id":"TextSentencer_T2","span":{"begin":155,"end":367},"obj":"Sentence"},{"id":"TextSentencer_T3","span":{"begin":368,"end":572},"obj":"Sentence"},{"id":"TextSentencer_T4","span":{"begin":573,"end":755},"obj":"Sentence"},{"id":"TextSentencer_T5","span":{"begin":756,"end":889},"obj":"Sentence"},{"id":"TextSentencer_T6","span":{"begin":890,"end":1114},"obj":"Sentence"},{"id":"TextSentencer_T7","span":{"begin":1115,"end":1469},"obj":"Sentence"},{"id":"TextSentencer_T8","span":{"begin":1470,"end":1613},"obj":"Sentence"},{"id":"TextSentencer_T9","span":{"begin":1614,"end":1710},"obj":"Sentence"},{"id":"TextSentencer_T10","span":{"begin":1711,"end":1942},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":154},"obj":"Sentence"},{"id":"T2","span":{"begin":155,"end":367},"obj":"Sentence"},{"id":"T3","span":{"begin":368,"end":572},"obj":"Sentence"},{"id":"T4","span":{"begin":573,"end":755},"obj":"Sentence"},{"id":"T5","span":{"begin":756,"end":889},"obj":"Sentence"},{"id":"T6","span":{"begin":890,"end":1114},"obj":"Sentence"},{"id":"T7","span":{"begin":1115,"end":1469},"obj":"Sentence"},{"id":"T8","span":{"begin":1470,"end":1613},"obj":"Sentence"},{"id":"T9","span":{"begin":1614,"end":1710},"obj":"Sentence"},{"id":"T10","span":{"begin":1711,"end":1942},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":79,"end":98},"obj":"gene:10724"},{"id":"T1","span":{"begin":139,"end":153},"obj":"disease:C0017083"},{"id":"T2","span":{"begin":172,"end":176},"obj":"gene:3073"},{"id":"T3","span":{"begin":285,"end":302},"obj":"disease:C0039373"},{"id":"T4","span":{"begin":213,"end":232},"obj":"gene:10724"},{"id":"T5","span":{"begin":285,"end":302},"obj":"disease:C0039373"},{"id":"T6","span":{"begin":213,"end":232},"obj":"gene:10724"},{"id":"T7","span":{"begin":344,"end":358},"obj":"disease:C0017083"},{"id":"T8","span":{"begin":213,"end":232},"obj":"gene:10724"},{"id":"T9","span":{"begin":304,"end":307},"obj":"disease:C0039373"},{"id":"T10","span":{"begin":668,"end":672},"obj":"gene:3073"},{"id":"T11","span":{"begin":740,"end":754},"obj":"disease:C0017083"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"},{"id":"R3","pred":"associated_with","subj":"T4","obj":"T5"},{"id":"R4","pred":"associated_with","subj":"T6","obj":"T7"},{"id":"R5","pred":"associated_with","subj":"T8","obj":"T9"},{"id":"R6","pred":"associated_with","subj":"T10","obj":"T11"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"DisGeNET5_variant_disease","denotations":[{"id":"9603435-0#0#5#geners121907981","span":{"begin":0,"end":5},"obj":"geners121907981"},{"id":"9603435-0#139#153#diseaseC0017083","span":{"begin":139,"end":153},"obj":"diseaseC0017083"},{"id":"9603435-6#9#14#geners121907981","span":{"begin":1124,"end":1129},"obj":"geners121907981"},{"id":"9603435-6#350#353#diseaseC0039373","span":{"begin":1465,"end":1468},"obj":"diseaseC0039373"}],"relations":[{"id":"0#5#geners121907981139#153#diseaseC0017083","pred":"associated_with","subj":"9603435-0#0#5#geners121907981","obj":"9603435-0#139#153#diseaseC0017083"},{"id":"9#14#geners121907981350#353#diseaseC0039373","pred":"associated_with","subj":"9603435-6#9#14#geners121907981","obj":"9603435-6#350#353#diseaseC0039373"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"DisGeNET5_gene_disease","denotations":[{"id":"9603435-0#79#98#gene10724","span":{"begin":79,"end":98},"obj":"gene10724"},{"id":"9603435-0#139#153#diseaseC0017083","span":{"begin":139,"end":153},"obj":"diseaseC0017083"},{"id":"9603435-1#58#77#gene10724","span":{"begin":213,"end":232},"obj":"gene10724"},{"id":"9603435-1#130#147#diseaseC0039373","span":{"begin":285,"end":302},"obj":"diseaseC0039373"},{"id":"9603435-3#95#99#gene3073","span":{"begin":668,"end":672},"obj":"gene3073"},{"id":"9603435-3#167#181#diseaseC0017083","span":{"begin":740,"end":754},"obj":"diseaseC0017083"}],"relations":[{"id":"79#98#gene10724139#153#diseaseC0017083","pred":"associated_with","subj":"9603435-0#79#98#gene10724","obj":"9603435-0#139#153#diseaseC0017083"},{"id":"58#77#gene10724130#147#diseaseC0039373","pred":"associated_with","subj":"9603435-1#58#77#gene10724","obj":"9603435-1#130#147#diseaseC0039373"},{"id":"95#99#gene3073167#181#diseaseC0017083","pred":"associated_with","subj":"9603435-3#95#99#gene3073","obj":"9603435-3#167#181#diseaseC0017083"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"PubCasesHPO","denotations":[{"id":"AB1","span":{"begin":1828,"end":1833},"obj":"HP:0002527"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"PubCasesORDO","denotations":[{"id":"AB1","span":{"begin":285,"end":302},"obj":"ORDO:845"}],"namespaces":[{"prefix":"ORDO","uri":"http://www.orpha.net/ORDO/Orphanet_"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBIDiseaseCorpus","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease:D020143"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease:D013661"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease:D013661"},{"id":"T4","span":{"begin":320,"end":366},"obj":"SpecificDisease:D020143"},{"id":"T5","span":{"begin":734,"end":754},"obj":"SpecificDisease:D020143"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease:D013661"},{"id":"T7","span":{"begin":1671,"end":1694},"obj":"SpecificDisease:D013661"},{"id":"T8","span":{"begin":1909,"end":1925},"obj":"SpecificDisease:D013661"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Test","denotations":[{"id":"T464","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T465","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T466","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T467","span":{"begin":320,"end":366},"obj":"SpecificDisease"},{"id":"T468","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T469","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"},{"id":"T470","span":{"begin":1671,"end":1694},"obj":"SpecificDisease"},{"id":"T471","span":{"begin":1909,"end":1925},"obj":"SpecificDisease"}],"attributes":[{"id":"A464","pred":"database_id","subj":"T464","obj":"D020143"},{"id":"A465","pred":"database_id","subj":"T465","obj":"D013661"},{"id":"A466","pred":"database_id","subj":"T466","obj":"D013661"},{"id":"A467","pred":"database_id","subj":"T467","obj":"D020143"},{"id":"A468","pred":"database_id","subj":"T468","obj":"D020143"},{"id":"A469","pred":"database_id","subj":"T469","obj":"D013661"},{"id":"A470","pred":"database_id","subj":"T470","obj":"D013661"},{"id":"A471","pred":"database_id","subj":"T471","obj":"D013661"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Test-Assistant-Knowledge","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"CompositeMention"},{"id":"T2","span":{"begin":285,"end":308},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":338,"end":366},"obj":"CompositeMention"},{"id":"T4","span":{"begin":381,"end":406},"obj":"Modifier"},{"id":"T5","span":{"begin":411,"end":432},"obj":"Modifier"},{"id":"T6","span":{"begin":714,"end":754},"obj":"CompositeMention"},{"id":"T7","span":{"begin":1455,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Test-4o-NoGuidelineInPrompt","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":308},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":381,"end":406},"obj":"Modifier"},{"id":"T5","span":{"begin":411,"end":432},"obj":"Modifier"},{"id":"T6","span":{"begin":714,"end":730},"obj":"Modifier"},{"id":"T7","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T8","span":{"begin":824,"end":849},"obj":"Modifier"},{"id":"T9","span":{"begin":1455,"end":1464},"obj":"Modifier"},{"id":"T10","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-o3-2","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":314,"end":366},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":714,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1455,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-high-o3-1","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":303,"end":308},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":358},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1455,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-high-o3-2","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":714,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1455,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Test-4o-GuidelineInPrompt","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-UpdatedGuideline","denotations":[{"id":"T1","span":{"begin":124,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-humanintheloop","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":358},"obj":"DiseaseClass"},{"id":"T5","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-rezarta1","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"DiseaseClass"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"DiseaseClass"},{"id":"T5","span":{"begin":734,"end":754},"obj":"DiseaseClass"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-All","denotations":[{"id":"T464","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T465","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T466","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T467","span":{"begin":320,"end":366},"obj":"SpecificDisease"},{"id":"T468","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T469","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"},{"id":"T470","span":{"begin":1671,"end":1694},"obj":"SpecificDisease"},{"id":"T471","span":{"begin":1909,"end":1925},"obj":"SpecificDisease"}],"attributes":[{"id":"A464","pred":"database_id","subj":"T464","obj":"D020143"},{"id":"A465","pred":"database_id","subj":"T465","obj":"D013661"},{"id":"A466","pred":"database_id","subj":"T466","obj":"D013661"},{"id":"A467","pred":"database_id","subj":"T467","obj":"D020143"},{"id":"A468","pred":"database_id","subj":"T468","obj":"D020143"},{"id":"A469","pred":"database_id","subj":"T469","obj":"D013661"},{"id":"A470","pred":"database_id","subj":"T470","obj":"D013661"},{"id":"A471","pred":"database_id","subj":"T471","obj":"D013661"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-2stage-All","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":358},"obj":"DiseaseClass"},{"id":"T5","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-rezarta-All","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T5","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-4oGuideline-All","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":308},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":338,"end":366},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":734,"end":754},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"NCBI-Disease-Corpus-Simple-All","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"CompositeMention"},{"id":"T2","span":{"begin":172,"end":176},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":285,"end":308},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"CompositeMention"},{"id":"T5","span":{"begin":381,"end":406},"obj":"Modifier"},{"id":"T6","span":{"begin":411,"end":432},"obj":"Modifier"},{"id":"T7","span":{"begin":668,"end":672},"obj":"SpecificDisease"},{"id":"T8","span":{"begin":714,"end":730},"obj":"Modifier"},{"id":"T9","span":{"begin":734,"end":754},"obj":"CompositeMention"},{"id":"T10","span":{"begin":1455,"end":1464},"obj":"Modifier"},{"id":"T11","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"123456","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"SpecificDisease"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":358},"obj":"DiseaseClass"},{"id":"T5","span":{"begin":734,"end":754},"obj":"SpecificDisease"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}

{"project":"12345","denotations":[{"id":"T1","span":{"begin":133,"end":153},"obj":"DiseaseClass"},{"id":"T2","span":{"begin":285,"end":302},"obj":"SpecificDisease"},{"id":"T3","span":{"begin":304,"end":307},"obj":"SpecificDisease"},{"id":"T4","span":{"begin":338,"end":366},"obj":"CompositeMention"},{"id":"T5","span":{"begin":734,"end":754},"obj":"DiseaseClass"},{"id":"T6","span":{"begin":1465,"end":1468},"obj":"SpecificDisease"}],"text":"W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis.\nMutations in the HEXA gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), that abolish Hex A enzyme activity cause Tay-Sachs disease (TSD), the fatal infantile form of G(M2) gangliosidosis, Type 1. Less severe, subacute (juvenile-onset) and chronic (adult-onset) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity. We identified a 1422 G--\u003eC (amino acid W474C) substitution in the first position of exon 13 of HEXA of a non-Jewish proband who manifested a subacute variant of G(M2) gangliosidosis. On the second maternally inherited allele, we identified the common infantile disease-causing 4-bp insertion, +TATC 1278, in exon 11. Pulse-chase analysis using proband fibroblasts revealed that the W474C-containing alpha-subunit precursor was normally synthesized, but not phosphorylated or secreted, and the mature lysosomal alpha-subunit was not detected. When the W474C-containing alpha-subunit was transiently co-expressed with the beta-subunit to produce Hex A (alphabeta) in COS-7 cells, the mature alpha-subunit was present, but its level was much lower than that from normal alpha-subunit transfections, although higher than in those cells transfected with an alpha-subunit associated with infantile TSD. Furthermore, the precursor level of the W474C alpha-subunit was found to accumulate in comparison to the normal alpha-subunit precursor levels. We conclude that the 1422 G--\u003eC mutation is the cause of Hex A enzyme deficiency in the proband. The resulting W474C substitution clearly interferes with alpha-subunit processing, but because the base substitution falls at the first position of exon 13, aberrant splicing may also contribute to Hex A deficiency in this proband."}