PubMed:8106452 JSONTXT

Annnotations TAB JSON ListView MergeView

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/8106452","sourcedb":"PubMed","sourceid":"8106452","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/8106452","text":"Preferential beta-hexosaminidase (Hex) A (alpha beta) formation in the absence of beta-Hex B (beta beta) due to heterozygous point mutations present in beta-Hex beta-chain alleles of a motor neuron disease patient.\nDeficiency of the lysosomal enzyme beta-hexosaminidase B (beta-Hex B) (a homodimer, beta beta), caused by a defect in the HEX B gene encoding the beta-chain, is usually accompanied by an absence of beta-Hex A (a heterodimer, alpha beta), thereby causing Sandhoff disease. However, we have earlier demonstrated the presence of partial beta-Hex A (30-50% of normal) even in the absence of beta-Hex B in an adult with motor neuron disease. The patient is a compound heterozygote with normal beta-chain message and one HEX B point mutation originating from each asymptomatic parent. Since the non-expression of beta-Hex B was post-transcriptional, we transfected COS-7 cells to understand the effect of each mutation on beta-Hex B activity. Transfection of the A1367--\u003eC mutant (maternal allele) construct produced no overexpressed beta-Hex B, indicating that the encoded Tyr456--\u003eSer beta-chain was non-functional. Chou-Fasman analysis predicted that the Tyr456--\u003eSer mutation would cause a dramatic change in beta-chain folding (which often inhibits formation of functional dimers). This explains the complete lack of beta-Hex B in the transfectants and a partial deficiency of beta-Hex A and B (50% of normal) in the patient's mother. Since immunoprecipitated beta-Hex A (alpha beta) protein from patient fibroblasts showed the presence of mature beta-chains even though there was no beta-Hex B (beta beta) protein, the mutant beta-chain inherited from the father (who has normal beta-Hex A and B) must undergo preferential association with the normal alpha-chains in the patient, thus producing only beta-Hex A. Transient expression of the A619--\u003eG mutant (paternal allele) construct produced beta-Hex B activity comparable to the wild type (approximately 10-20-fold over mock-transfected) whereas stable expression produced normal message but no beta-Hex B activity (wild type beta-Hex B expression: only 2-fold over mock-transfected). The lack of increased beta-Hex B after stable expression of the Ile207--\u003eVal beta-chains at a lower copy number indicates the absence of self-association at low concentrations of Ile207--\u003eVal beta-chain. In the patient who also has a non-functional Tyr456--\u003eSer allele, the effective concentration of beta-chains is reduced to 50% of normal and the remaining Ile207--\u003eVal beta-chains fail to self-associate but can still dimerize with the abundant normal alpha-chains thus producing partial beta-Hex A and no beta-Hex B.","tracks":[{"project":"PubTator4TogoVar","denotations":[{"id":"8106452_0","span":{"begin":1083,"end":1095},"obj":"ProteinMutation"},{"id":"8106452_1","span":{"begin":1167,"end":1179},"obj":"ProteinMutation"},{"id":"8106452_2","span":{"begin":2216,"end":2228},"obj":"ProteinMutation"},{"id":"8106452_3","span":{"begin":2331,"end":2343},"obj":"ProteinMutation"},{"id":"8106452_4","span":{"begin":2401,"end":2413},"obj":"ProteinMutation"},{"id":"8106452_5","span":{"begin":2511,"end":2523},"obj":"ProteinMutation"}],"attributes":[{"id":"8106452_0_ProteinMutation","pred":"proteinmutation","subj":"8106452_0","obj":"rs121907982"},{"id":"8106452_1_ProteinMutation","pred":"proteinmutation","subj":"8106452_1","obj":"rs121907982"},{"id":"8106452_2_ProteinMutation","pred":"proteinmutation","subj":"8106452_2","obj":"rs10805890"},{"id":"8106452_3_ProteinMutation","pred":"proteinmutation","subj":"8106452_3","obj":"rs10805890"},{"id":"8106452_4_ProteinMutation","pred":"proteinmutation","subj":"8106452_4","obj":"rs121907982"},{"id":"8106452_5_ProteinMutation","pred":"proteinmutation","subj":"8106452_5","obj":"rs10805890"},{"subj":"8106452_0","pred":"source","obj":"PubTator4TogoVar"},{"subj":"8106452_1","pred":"source","obj":"PubTator4TogoVar"},{"subj":"8106452_2","pred":"source","obj":"PubTator4TogoVar"},{"subj":"8106452_3","pred":"source","obj":"PubTator4TogoVar"},{"subj":"8106452_4","pred":"source","obj":"PubTator4TogoVar"},{"subj":"8106452_5","pred":"source","obj":"PubTator4TogoVar"}]},{"project":"sentences","denotations":[{"id":"TextSentencer_T1","span":{"begin":0,"end":214},"obj":"Sentence"},{"id":"TextSentencer_T2","span":{"begin":215,"end":486},"obj":"Sentence"},{"id":"TextSentencer_T3","span":{"begin":487,"end":651},"obj":"Sentence"},{"id":"TextSentencer_T4","span":{"begin":652,"end":793},"obj":"Sentence"},{"id":"TextSentencer_T5","span":{"begin":794,"end":951},"obj":"Sentence"},{"id":"TextSentencer_T6","span":{"begin":952,"end":1126},"obj":"Sentence"},{"id":"TextSentencer_T7","span":{"begin":1127,"end":1295},"obj":"Sentence"},{"id":"TextSentencer_T8","span":{"begin":1296,"end":1448},"obj":"Sentence"},{"id":"TextSentencer_T9","span":{"begin":1449,"end":1826},"obj":"Sentence"},{"id":"TextSentencer_T10","span":{"begin":1827,"end":2151},"obj":"Sentence"},{"id":"TextSentencer_T11","span":{"begin":2152,"end":2355},"obj":"Sentence"},{"id":"TextSentencer_T12","span":{"begin":2356,"end":2672},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":214},"obj":"Sentence"},{"id":"T2","span":{"begin":215,"end":486},"obj":"Sentence"},{"id":"T3","span":{"begin":487,"end":651},"obj":"Sentence"},{"id":"T4","span":{"begin":652,"end":793},"obj":"Sentence"},{"id":"T5","span":{"begin":794,"end":951},"obj":"Sentence"},{"id":"T6","span":{"begin":952,"end":1126},"obj":"Sentence"},{"id":"T7","span":{"begin":1127,"end":1295},"obj":"Sentence"},{"id":"T8","span":{"begin":1296,"end":1448},"obj":"Sentence"},{"id":"T9","span":{"begin":1449,"end":1826},"obj":"Sentence"},{"id":"T10","span":{"begin":1827,"end":2151},"obj":"Sentence"},{"id":"T11","span":{"begin":2152,"end":2355},"obj":"Sentence"},{"id":"T12","span":{"begin":2356,"end":2672},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"attributes":[{"subj":"TextSentencer_T1","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T2","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T3","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T4","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T5","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T6","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T7","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T8","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T9","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T10","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T11","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T12","pred":"source","obj":"sentences"},{"subj":"T1","pred":"source","obj":"sentences"},{"subj":"T2","pred":"source","obj":"sentences"},{"subj":"T3","pred":"source","obj":"sentences"},{"subj":"T4","pred":"source","obj":"sentences"},{"subj":"T5","pred":"source","obj":"sentences"},{"subj":"T6","pred":"source","obj":"sentences"},{"subj":"T7","pred":"source","obj":"sentences"},{"subj":"T8","pred":"source","obj":"sentences"},{"subj":"T9","pred":"source","obj":"sentences"},{"subj":"T10","pred":"source","obj":"sentences"},{"subj":"T11","pred":"source","obj":"sentences"},{"subj":"T12","pred":"source","obj":"sentences"}]},{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":87,"end":90},"obj":"gene:10724"},{"id":"T1","span":{"begin":185,"end":205},"obj":"disease:C0085084"},{"id":"T2","span":{"begin":34,"end":37},"obj":"gene:10724"},{"id":"T3","span":{"begin":185,"end":205},"obj":"disease:C0085084"},{"id":"T4","span":{"begin":13,"end":32},"obj":"gene:10724"},{"id":"T5","span":{"begin":185,"end":205},"obj":"disease:C0085084"},{"id":"T6","span":{"begin":607,"end":610},"obj":"gene:10724"},{"id":"T7","span":{"begin":630,"end":650},"obj":"disease:C0085084"},{"id":"T8","span":{"begin":554,"end":557},"obj":"gene:10724"},{"id":"T9","span":{"begin":630,"end":650},"obj":"disease:C0085084"}],"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"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"attributes":[{"subj":"T0","pred":"source","obj":"DisGeNET"},{"subj":"T1","pred":"source","obj":"DisGeNET"},{"subj":"T2","pred":"source","obj":"DisGeNET"},{"subj":"T3","pred":"source","obj":"DisGeNET"},{"subj":"T4","pred":"source","obj":"DisGeNET"},{"subj":"T5","pred":"source","obj":"DisGeNET"},{"subj":"T6","pred":"source","obj":"DisGeNET"},{"subj":"T7","pred":"source","obj":"DisGeNET"},{"subj":"T8","pred":"source","obj":"DisGeNET"},{"subj":"T9","pred":"source","obj":"DisGeNET"}]},{"project":"DisGeNET5_gene_disease","denotations":[{"id":"8106452-0#13#32#gene10724","span":{"begin":13,"end":32},"obj":"gene10724"},{"id":"8106452-0#34#37#gene10724","span":{"begin":34,"end":37},"obj":"gene10724"},{"id":"8106452-0#87#90#gene10724","span":{"begin":87,"end":90},"obj":"gene10724"},{"id":"8106452-0#185#205#diseaseC0085084","span":{"begin":185,"end":205},"obj":"diseaseC0085084"},{"id":"8106452-1#35#54#gene10724","span":{"begin":250,"end":269},"obj":"gene10724"},{"id":"8106452-1#203#206#gene10724","span":{"begin":418,"end":421},"obj":"gene10724"},{"id":"8106452-1#254#270#diseaseC0036161","span":{"begin":469,"end":485},"obj":"diseaseC0036161"}],"relations":[{"id":"13#32#gene10724185#205#diseaseC0085084","pred":"associated_with","subj":"8106452-0#13#32#gene10724","obj":"8106452-0#185#205#diseaseC0085084"},{"id":"34#37#gene10724185#205#diseaseC0085084","pred":"associated_with","subj":"8106452-0#34#37#gene10724","obj":"8106452-0#185#205#diseaseC0085084"},{"id":"87#90#gene10724185#205#diseaseC0085084","pred":"associated_with","subj":"8106452-0#87#90#gene10724","obj":"8106452-0#185#205#diseaseC0085084"},{"id":"35#54#gene10724254#270#diseaseC0036161","pred":"associated_with","subj":"8106452-1#35#54#gene10724","obj":"8106452-1#254#270#diseaseC0036161"},{"id":"203#206#gene10724254#270#diseaseC0036161","pred":"associated_with","subj":"8106452-1#203#206#gene10724","obj":"8106452-1#254#270#diseaseC0036161"}],"attributes":[{"subj":"8106452-0#13#32#gene10724","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"8106452-0#34#37#gene10724","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"8106452-0#87#90#gene10724","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"8106452-0#185#205#diseaseC0085084","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"8106452-1#35#54#gene10724","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"8106452-1#203#206#gene10724","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"8106452-1#254#270#diseaseC0036161","pred":"source","obj":"DisGeNET5_gene_disease"}]},{"project":"PubCasesORDO","denotations":[{"id":"AB1","span":{"begin":469,"end":485},"obj":"ORDO:796"}],"namespaces":[{"prefix":"ORDO","uri":"http://www.orpha.net/ORDO/Orphanet_"}],"attributes":[{"subj":"AB1","pred":"source","obj":"PubCasesORDO"}]},{"project":"performance-test","denotations":[{"id":"PD-UBERON-AE-B_T1","span":{"begin":191,"end":197},"obj":"http://purl.obolibrary.org/obo/UBERON_2000602"},{"id":"PD-UBERON-AE-B_T2","span":{"begin":636,"end":642},"obj":"http://purl.obolibrary.org/obo/UBERON_2000602"}],"attributes":[{"subj":"PD-UBERON-AE-B_T1","pred":"source","obj":"performance-test"},{"subj":"PD-UBERON-AE-B_T2","pred":"source","obj":"performance-test"}]},{"project":"mondo_disease","denotations":[{"id":"T1","span":{"begin":185,"end":205},"obj":"Disease"},{"id":"T2","span":{"begin":469,"end":485},"obj":"Disease"},{"id":"T3","span":{"begin":630,"end":650},"obj":"Disease"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/MONDO_0020128"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/MONDO_0010006"},{"id":"A3","pred":"mondo_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/MONDO_0020128"},{"subj":"T1","pred":"source","obj":"mondo_disease"},{"subj":"T2","pred":"source","obj":"mondo_disease"},{"subj":"T3","pred":"source","obj":"mondo_disease"}]},{"project":"NCBITAXON","denotations":[{"id":"T1","span":{"begin":206,"end":213},"obj":"OrganismTaxon"},{"id":"T2","span":{"begin":656,"end":663},"obj":"OrganismTaxon"},{"id":"T3","span":{"begin":1511,"end":1518},"obj":"OrganismTaxon"},{"id":"T4","span":{"begin":1786,"end":1793},"obj":"OrganismTaxon"},{"id":"T5","span":{"begin":2363,"end":2370},"obj":"OrganismTaxon"}],"attributes":[{"id":"A1","pred":"db_id","subj":"T1","obj":"9606"},{"id":"A2","pred":"db_id","subj":"T2","obj":"9606"},{"id":"A3","pred":"db_id","subj":"T3","obj":"9606"},{"id":"A4","pred":"db_id","subj":"T4","obj":"9606"},{"id":"A5","pred":"db_id","subj":"T5","obj":"9606"},{"subj":"T1","pred":"source","obj":"NCBITAXON"},{"subj":"T2","pred":"source","obj":"NCBITAXON"},{"subj":"T3","pred":"source","obj":"NCBITAXON"},{"subj":"T4","pred":"source","obj":"NCBITAXON"},{"subj":"T5","pred":"source","obj":"NCBITAXON"}]},{"project":"Anatomy-UBERON","denotations":[{"id":"T1","span":{"begin":185,"end":197},"obj":"Body_part"},{"id":"T2","span":{"begin":630,"end":642},"obj":"Body_part"},{"id":"T3","span":{"begin":1519,"end":1530},"obj":"Body_part"}],"attributes":[{"id":"A1","pred":"uberon_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL_0000100"},{"id":"A2","pred":"uberon_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/CL_0000100"},{"id":"A3","pred":"uberon_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/CL_0000057"},{"subj":"T1","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T2","pred":"source","obj":"Anatomy-UBERON"},{"subj":"T3","pred":"source","obj":"Anatomy-UBERON"}]},{"project":"CL-cell","denotations":[{"id":"T1","span":{"begin":185,"end":197},"obj":"Cell"},{"id":"T2","span":{"begin":191,"end":197},"obj":"Cell"},{"id":"T3","span":{"begin":630,"end":642},"obj":"Cell"},{"id":"T4","span":{"begin":636,"end":642},"obj":"Cell"},{"id":"T5","span":{"begin":1519,"end":1530},"obj":"Cell"}],"attributes":[{"id":"A1","pred":"cl_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL:0000100"},{"id":"A2","pred":"cl_id","subj":"T2","obj":"http://purl.obolibrary.org/obo/CL:0000540"},{"id":"A3","pred":"cl_id","subj":"T3","obj":"http://purl.obolibrary.org/obo/CL:0000100"},{"id":"A4","pred":"cl_id","subj":"T4","obj":"http://purl.obolibrary.org/obo/CL:0000540"},{"id":"A5","pred":"cl_id","subj":"T5","obj":"http://purl.obolibrary.org/obo/CL:0000057"},{"subj":"T1","pred":"source","obj":"CL-cell"},{"subj":"T2","pred":"source","obj":"CL-cell"},{"subj":"T3","pred":"source","obj":"CL-cell"},{"subj":"T4","pred":"source","obj":"CL-cell"},{"subj":"T5","pred":"source","obj":"CL-cell"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"PubTator4TogoVar","color":"#93eceb","default":true},{"id":"sentences","color":"#ecd193"},{"id":"DisGeNET","color":"#b793ec"},{"id":"DisGeNET5_gene_disease","color":"#93ec9d"},{"id":"PubCasesORDO","color":"#ec93a3"},{"id":"performance-test","color":"#93bdec"},{"id":"mondo_disease","color":"#d7ec93"},{"id":"NCBITAXON","color":"#e793ec"},{"id":"Anatomy-UBERON","color":"#93eccd"},{"id":"CL-cell","color":"#ecb393"}]}]}}