Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene
The structure of the gene for protein C, an anticoagulant serine protease, was analyzed in 29 unrelated patients with hereditary thrombophilia and protein C deficiency. Gene deletion(s) or gross rearrangement(s) was not demonstrable by Southern blot hybridization to cDNA probes. However, two unrelated patients showed a variant restriction pattern after Pvu II or BamHi digestion, due to mutations in the last exon: analysis of their pedigrees, including three or seven heterozygotes, respectively, with approx.50% reduction of both enzymatic and antigen level, showed the abnormal restriction pattern in all heterozygous individuals, but not in normal relatives. Cloning of protein C gene and sequencing of the last exon allowed the authors to identify a nonsense and a missense mutation, respectively. In the first case, codon 306 (CGA, arginine) is mutated to an inframe stop codon, thus generating a new Pvu II recognition site. In the second case, a missense mutation in the BamHI palindrome (GGATCC ..-->.. GCATCC) leads to substitution of a key amino acid (a tryptophan to cysteine substitution at position 402), invariantly conserved in eukaryotic serine proteases. These point mutations may explain the protein C-deficiency phenotype of heterozygotes in the two pedigrees.
- Research Organization:
- European Molecular Biology Lab., Heidelberg, West Germany
- OSTI ID:
- 5877395
- Journal Information:
- Proc. Natl. Acad. Sci. U.S.A.; (United States), Vol. 84:9
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
GENES
DNA SEQUENCING
DNA-CLONING
HEREDITARY DISEASES
PATHOGENESIS
SERINE PROTEINASES
GENE MUTATIONS
HEMIC DISEASES
PATIENTS
PHENOTYPE
PHOSPHORUS 32
RECOMBINANT DNA
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
CLONING
DAYS LIVING RADIOISOTOPES
DISEASES
DNA
ENZYMES
HYDROLASES
ISOTOPES
LIGHT NUCLEI
MUTATIONS
NUCLEI
NUCLEIC ACIDS
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
PEPTIDE HYDROLASES
PHOSPHORUS ISOTOPES
RADIOISOTOPES
STRUCTURAL CHEMICAL ANALYSIS
550401* - Genetics- Tracer Techniques