Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
7
|
| pubmed:dateCreated |
1994-3-22
|
| pubmed:abstractText |
Deficiency 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-->C mutant (maternal allele) construct produced no overexpressed beta-Hex B, indicating that the encoded Tyr456-->Ser beta-chain was non-functional. Chou-Fasman analysis predicted that the Tyr456-->Ser 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-->G 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-->Val beta-chains at a lower copy number indicates the absence of self-association at low concentrations of Ile207-->Val beta-chain. In the patient who also has a non-functional Tyr456-->Ser allele, the effective concentration of beta-chains is reduced to 50% of normal and the remaining Ile207-->Val 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.
|
| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Hexosaminidase A,
http://linkedlifedata.com/resource/pubmed/chemical/Hexosaminidase B,
http://linkedlifedata.com/resource/pubmed/chemical/Macromolecular Substances,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/beta-N-Acetylhexosaminidases
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Feb
|
| pubmed:issn |
0021-9258
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
18
|
| pubmed:volume |
269
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
4819-26
|
| pubmed:dateRevised |
2007-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:8106452-Adult,
pubmed-meshheading:8106452-Alleles,
pubmed-meshheading:8106452-Amino Acid Sequence,
pubmed-meshheading:8106452-Animals,
pubmed-meshheading:8106452-Cell Line,
pubmed-meshheading:8106452-Exons,
pubmed-meshheading:8106452-Female,
pubmed-meshheading:8106452-Heterozygote Detection,
pubmed-meshheading:8106452-Hexosaminidase A,
pubmed-meshheading:8106452-Hexosaminidase B,
pubmed-meshheading:8106452-Humans,
pubmed-meshheading:8106452-Macromolecular Substances,
pubmed-meshheading:8106452-Male,
pubmed-meshheading:8106452-Motor Neuron Disease,
pubmed-meshheading:8106452-Point Mutation,
pubmed-meshheading:8106452-Protein Structure, Secondary,
pubmed-meshheading:8106452-Sandhoff Disease,
pubmed-meshheading:8106452-Serine,
pubmed-meshheading:8106452-Transfection,
pubmed-meshheading:8106452-Tyrosine,
pubmed-meshheading:8106452-beta-N-Acetylhexosaminidases
|
| pubmed:year |
1994
|
| pubmed:articleTitle |
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.
|
| pubmed:affiliation |
Department of Pediatrics, University of Chicago, Illinois 60637.
|
| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Case Reports
|