GENETIC MUTATIONS IN 10 UNRELATED AMERICAN PATIENTS WITH SYMPTOMATIC TYPE-1 PROTEIN-C DEFICIENCY

Symptomatic patients with Type 1 protein C deficiency and venous throm bosis were analysed for defects in this gene using polymerase chain re action amplification and direct sequencing of all nine exons. Ten diff erent heterozygous point mutations were detected in 19 patients from e leven American families. Seven represent novel mutations. Two of these were found in the TATA box or near the transcription initiation site and presumably lead to loss of transcription, and seven missense mutat ions were found including G103R, P168L, R169W, I201T, P279L, T298M, an d C384Y. These may lead to abnormal folding or thermodynamic instabili ty of the protein C molecule, potentially causing abnormal secretion o r rapid clearance from the circulation. Two other protein C mutations, a nonsense mutation at codon Trp-145 and a deletion inducing a frames hift at codon 364 resulting in premature termination at codon 378, lik ely lead to unstable products. The previously published R169W mutation resulted in a Type 1 deficiency. The data show that diverse molecular defects result in similar phenotypes and emphasize that a wide variet y of mutations are responsible for Type 1 protein C deficiency in the American setting of a diverse population.