First de novo mutations in the protein C gene of two patients with type I deficiency: A missense mutation and a splice site deletion

Abstract

In a series of 40 patients with symptomatic protein C deficiency, we identified two sporadic cases with novel mutations that probably affect gene expression. The mutations, a 5-bp deletion of the donor splice site of intron f (nucleotides 3455 to 3459) and a mutation of nucleotide 8523 in exon IX leading to the substitution of Ser 270 by Pro, were not found in the protein C gene of the patients' parents. Transmission of the paternal and maternal protein C alleles was apparently normal on the basis of frequent polymorphisms in exons I, VI, and VIII. We also checked the transmission of the chromosomal material by analyzing the β-globin gene frameworks and three variable number of tandem repeats (VNTRs). By combining the results of intragenic polymorphism, VNTR and β-globin gene framework analyses, we were able to exclude nonpaternity and confirm the de novo origin of the mutation.