title: Hypofibrinogenaemia with compound heterozygosity for two gamma chain mutations - gamma 82 Ala-->Gly and an intron two GT-->AT splice site mutation.
abstract: We investigated the molecular basis of hypofibrinogenaemia in a woman with a history of recurrent, pregnancy-associated bleeding, and miscarriage. She had a Clauss fibrinogen of 0.9 mg/ml and SDS PAGE of purified fibrinogen showed a normal pattern of chains. However careful inspection of reverse phase chain separation profiles showed apparent homozygosity for a more hydrophilic form of the gamma chain. DNA Sequencing showed only heterozygosity for a CGT-->GGT (Ala-->Gly) mutation at codon gamma82, but further sequencing showed an additional GT splice sequence mutation at the 5' end of intron 2 of the gamma gene. Translation of mRNA containing this intron would result in premature truncation explaining the phenotypic homozygosity of the gamma82 Ala-->Gly substitution. The patient's sister had a mild bleeding disorder with hypofibrinogenaemia and she too was a compound heterozygote for the y mutations. Her nephew had only the novel splice site mutation, while her mother and daughter inherited only the gamma82 Ala-->Gly substitution.
authors.affiliation: Molecular Pathology Laboratory, Christchurch Hospital, New Zealand.
authors.forename: J
authors.initials: J
authors.lastname: Wyatt
authors.forename: S O
authors.initials: SO
authors.lastname: Brennan
authors.forename: S
authors.initials: S
authors.lastname: May
authors.forename: P M
authors.initials: PM
authors.lastname: George
mesh_terms: D000328:Adult; D000347:Afibrinogenemia / Q000235:genetics*; D019943:Amino Acid Substitution; D001483:Base Sequence; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005340:Fibrinogen / Q000235:genetics; D006470:Hemorrhage / Q000209:etiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000209:etiology; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D022821:RNA Splice Sites; D005340:Fibrinogen