HOMOZYGOSITY FOR R87H MISSENSE MUTATION AND FOR A RARE INTRON-7 DNA VARIANT (7054G-]A) IN THE PROC GENES OF 3 SIBLINGS INITIALLY CLASSIFIEDAS HETEROZYGOTES FOR PROTEIN-C DEFICIENCY

We report the results of protein C gene (PROC) analysis in a Spanish f amily with hereditary PC deficiency characterized by the presence of t hree siblings with PC anticoagulant activity levels clearly below 50% of normal and PC antigen and amidolytic activities between 50 and 75% of normal. Their parents are first cousins and have PC levels between 50 and 80% of normal. Sequence analysis of the whole coding sequence o f the PROC gene revealed that the three siblings are double homozygote s for a G to A transition at nucleotide 3203 that replaces arginine 87 by histidine (R87H) and for another G to A transition at nucleotide 7 054, in intron 7 (7054G --> A). Both parents and one sister were found to be double heterozygotes for these two mutations. Screening for the intronic mutation in a control group and RT-PCR cDNA studies from ect opically transcribed mRNA indicated that 7054G --> A is most likely a rare but neutral DNA variant. These results and the fact that heterozy gosity for the missense R87H mutation has also been found associated w ith a slightly decreased PC anticoagulant activity in another Spanish family, lead us to conclude that homozygosity for R87H is responsible for the PC deficient phenotype in these three siblings.