PubMed:19592582 JSONTXT

{"project":"TEST-DiseaseOrPhenotypicFeature","denotations":[{"id":"T1","span":{"begin":26,"end":64},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":234,"end":272},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T3","span":{"begin":274,"end":279},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":443,"end":448},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T5","span":{"begin":1220,"end":1225},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T6","span":{"begin":1402,"end":1417},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"#label","subj":"T1","obj":"C562385"},{"id":"A2","pred":"#label","subj":"T2","obj":"C562385"},{"id":"A3","pred":"#label","subj":"T3","obj":"D018798"},{"id":"A4","pred":"#label","subj":"T4","obj":"D018798"},{"id":"A5","pred":"#label","subj":"T5","obj":"D018798"},{"id":"A6","pred":"#label","subj":"T6","obj":"D000090463"}],"text":"Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.\nMutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C\u003eA and c.468C\u003eT in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency."}

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{"project":"Test-SequenceVariant","denotations":[{"id":"T1","span":{"begin":498,"end":504},"obj":"SequenceVariant"},{"id":"T2","span":{"begin":576,"end":587},"obj":"SequenceVariant"},{"id":"T3","span":{"begin":715,"end":723},"obj":"SequenceVariant"},{"id":"T4","span":{"begin":728,"end":736},"obj":"SequenceVariant"},{"id":"T5","span":{"begin":781,"end":786},"obj":"SequenceVariant"},{"id":"T6","span":{"begin":1025,"end":1030},"obj":"SequenceVariant"}],"text":"Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.\nMutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C\u003eA and c.468C\u003eT in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency."}

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mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.\nMutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C\u003eA and c.468C\u003eT in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency."}

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{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":0,"end":12},"obj":"gene:164656"},{"id":"T1","span":{"begin":26,"end":64},"obj":"disease:C0085576"},{"id":"T2","span":{"begin":167,"end":179},"obj":"gene:164656"},{"id":"T3","span":{"begin":234,"end":272},"obj":"disease:C0085576"},{"id":"T4","span":{"begin":167,"end":179},"obj":"gene:164656"},{"id":"T5","span":{"begin":274,"end":279},"obj":"disease:C0085576"},{"id":"T6","span":{"begin":297,"end":305},"obj":"gene:57817"},{"id":"T7","span":{"begin":274,"end":279},"obj":"disease:C0085576"},{"id":"T8","span":{"begin":297,"end":305},"obj":"gene:57817"},{"id":"T9","span":{"begin":234,"end":272},"obj":"disease:C0085576"},{"id":"T10","span":{"begin":389,"end":396},"obj":"gene:164656"},{"id":"T11","span":{"begin":443,"end":448},"obj":"disease:C0085576"},{"id":"T12","span":{"begin":375,"end":387},"obj":"gene:164656"},{"id":"T13","span":{"begin":443,"end":448},"obj":"disease:C0085576"},{"id":"T14","span":{"begin":1186,"end":1193},"obj":"gene:164656"},{"id":"T15","span":{"begin":1220,"end":1225},"obj":"disease:C0085576"},{"id":"T16","span":{"begin":1186,"end":1193},"obj":"gene:164656"},{"id":"T17","span":{"begin":1402,"end":1417},"obj":"disease:C0240066"},{"id":"T18","span":{"begin":1382,"end":1394},"obj":"gene:164656"},{"id":"T19","span":{"begin":1220,"end":1225},"obj":"disease:C0085576"},{"id":"T20","span":{"begin":1382,"end":1394},"obj":"gene:164656"},{"id":"T21","span":{"begin":1402,"end":1417},"obj":"disease:C0240066"}],"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"},{"id":"R7","pred":"associated_with","subj":"T12","obj":"T13"},{"id":"R8","pred":"associated_with","subj":"T14","obj":"T15"},{"id":"R9","pred":"associated_with","subj":"T16","obj":"T17"},{"id":"R10","pred":"associated_with","subj":"T18","obj":"T19"},{"id":"R11","pred":"associated_with","subj":"T20","obj":"T21"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"text":"Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.\nMutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C\u003eA and c.468C\u003eT in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency."}

{"project":"DisGeNET5_gene_disease","denotations":[{"id":"19592582-0#0#12#gene164656","span":{"begin":0,"end":12},"obj":"gene164656"},{"id":"19592582-0#26#64#diseaseC0085576","span":{"begin":26,"end":64},"obj":"diseaseC0085576"},{"id":"19592582-1#165#173#gene57817","span":{"begin":297,"end":305},"obj":"gene57817"},{"id":"19592582-1#102#140#diseaseC0085576","span":{"begin":234,"end":272},"obj":"diseaseC0085576"},{"id":"19592582-1#142#147#diseaseC0085576","span":{"begin":274,"end":279},"obj":"diseaseC0085576"},{"id":"19592582-7#50#57#gene164656","span":{"begin":1186,"end":1193},"obj":"gene164656"},{"id":"19592582-7#246#258#gene164656","span":{"begin":1382,"end":1394},"obj":"gene164656"},{"id":"19592582-7#266#281#diseaseC0240066","span":{"begin":1402,"end":1417},"obj":"diseaseC0240066"}],"relations":[{"id":"0#12#gene16465626#64#diseaseC0085576","pred":"associated_with","subj":"19592582-0#0#12#gene164656","obj":"19592582-0#26#64#diseaseC0085576"},{"id":"165#173#gene57817102#140#diseaseC0085576","pred":"associated_with","subj":"19592582-1#165#173#gene57817","obj":"19592582-1#102#140#diseaseC0085576"},{"id":"165#173#gene57817142#147#diseaseC0085576","pred":"associated_with","subj":"19592582-1#165#173#gene57817","obj":"19592582-1#142#147#diseaseC0085576"},{"id":"50#57#gene164656266#281#diseaseC0240066","pred":"associated_with","subj":"19592582-7#50#57#gene164656","obj":"19592582-7#266#281#diseaseC0240066"},{"id":"246#258#gene164656266#281#diseaseC0240066","pred":"associated_with","subj":"19592582-7#246#258#gene164656","obj":"19592582-7#266#281#diseaseC0240066"}],"text":"Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.\nMutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C\u003eA and c.468C\u003eT in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency."}

{"project":"tmVarCorpus","denotations":[{"id":"T1","span":{"begin":498,"end":504},"obj":"ProteinMutation:p|FS|P|686||"},{"id":"T2","span":{"begin":571,"end":587},"obj":"DNAMutation:c|INS|2172_2173|CCCC"},{"id":"T3","span":{"begin":715,"end":723},"obj":"DNAMutation:c|SUB|C|467|A"},{"id":"T4","span":{"begin":728,"end":736},"obj":"DNAMutation:c|SUB|C|468|T"},{"id":"T5","span":{"begin":781,"end":786},"obj":"ProteinMutation:p|SUB|A|118|D"},{"id":"T6","span":{"begin":1025,"end":1030},"obj":"ProteinMutation:p|SUB|A|118|D"}],"text":"Matriptase-2 mutations in iron-refractory iron deficiency anemia patients provide new insights into protease activation mechanisms.\nMutations leading to abrogation of matriptase-2 proteolytic activity in humans are associated with an iron-refractory iron deficiency anemia (IRIDA) due to elevated hepcidin levels. Here we describe two novel heterozygous mutations within the matriptase-2 (TMPRSS6) gene of monozygotic twin girls exhibiting an IRIDA phenotype. The first is the frameshift mutation (P686fs) caused by the insertion of the four nucleotides CCCC in exon 16 (2172_2173insCCCC) that is predicted to terminate translation before the catalytic serine. The second mutation is the di-nucleotide substitution c.467C\u003eA and c.468C\u003eT in exon 3 that causes the missense mutation A118D in the SEA domain of the extracellular stem region of matriptase-2. Functional analysis of both variant matriptase-2 proteases has revealed that they lead to ineffective suppression of hepcidin transcription. We also demonstrate that the A118D SEA domain mutation causes an intra-molecular structural imbalance that impairs matriptase-2 activation. Collectively, these results extend the pattern of TMPRSS6 mutations associated with IRIDA and functionally demonstrate that mutations affecting protease regions other than the catalytic domain may have a profound impact in the regulatory role of matriptase-2 during iron deficiency."}