SEVERE TYPE-I PROTEIN-C DEFICIENCY IN A COMPOUND HETEROZYGOTE FOR Y124C AND Q132X MUTATIONS IN EXON-6 OF THE PROC GENE

We report the genetic abnormalities in the protein C genes of a Spanis h child with neonatal purpura fulminans and disseminated intravascular coagulation, associated with undetectable protein C levels. Direct se quencing of the nine protein C gene exons and their splice junctions i ndicated that the proband is a compound heterozygote with two mutant p rotein C gene alleles, Y124C and Q132X, that do not express protein C in plasma. The Y124C mutation was inherited from the mother and is due to a novel A to G transition at nucleotide 3416, which results in the substitution of cysteine for tyrosine 124, a highly conserved amino a cid in EGF-like domains. The paternal inherited. mutation (Q132X) is a C to T transition at nucleotide 3439, which replaces glutamine 132 wi th a Stop codon signal. This mutation, if expressed, should result in the synthesis of a truncated protein of 131 amino acids. Y124C or Q132 X are present in the heterozygous state in the asymptomatic parents an d siblings of the proband, all of which have half the normal plasma le vels of protein C. Q123X has also been identified in families where ty pe I PC deficiency is inherited as a clinically dominant trait. Theref ore, the presence of the same mutation in a family showing a clinicall y recessive pattern of inheritance indicates that other factors, apart from the type of protein C gene mutation, are responsible for the cli nical expression of protein C deficiency.