Human triosephosphate isomerase deficiency resulting from mutation of Phe-240
- Roswell Park Cancer Inst., Buffalo, NY (United States)
- Univ. of Sheffield (United Kingdom)
- National Inst. of Hematology and Blood Transfusion, Budapest (Hungary)
- Children's Hospital, Sydney (Australia)
Triosephosphate isomerase (TPI; D-glyceraldehyde-3-phosphate ketolisomerase [E.C.5.3.1.1]) deficiency is an autosomal recessive disorder that typically results in chronic, nonspherocytic hemolytic anemia and in neuromuscular impairment. The molecular basis of this disease was analyzed for one Hungarian family and for two Australian families by localizing the defects in TPI cDNA and by determining how each defect affects TPI gene expression. The Hungarian family is noteworthy in having the first reported case of an individual, A. Jo., who harbors two defective TPI alleles but who does not manifest neuromuscular disabilities. This family was characterized by two mutations that have never been described. One is a missense mutation within codon 240 (TTC [Phe][r arrow]CTC [Leu]), which creates a thermolabile protein, as indicated by the results of enzyme activity assays using cell extracts. This substitution, which changes a phylogenetically conserved amino acid, may affect enzyme activity by dusrupting intersubunit contacts or substrate binding, as deduced from enzyme structural studies. The other mutation has yet to be localized but reduces the abundance of TPI mRNA 10--20-fold. Each of the Australian families was characterized by a previously described mutation within codon 104 (GAG [Glu][r arrow]GAC [Asp]), which also results in thermolabile protein. 49 refs., 6 figs., 1 tab.
- OSTI ID:
- 6180545
- Journal Information:
- American Journal of Human Genetics; (United States), Vol. 52:6; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANEMIAS
GENE MUTATIONS
ISOMERASES
STRUCTURE-ACTIVITY RELATIONSHIPS
NERVOUS SYSTEM DISEASES
AMINO ACID SEQUENCE
DISEASES
GENE REGULATION
HEREDITARY DISEASES
LEUCINE
MOLECULAR STRUCTURE
MUSCLES
PHENYLALANINE
AMINO ACIDS
CARBOXYLIC ACIDS
ENZYMES
HEMIC DISEASES
MUTATIONS
ORGANIC ACIDS
ORGANIC COMPOUNDS
PROTEINS
SYMPTOMS
550400* - Genetics