2 DISTINCT NOVEL SPLICE-SITE MUTATIONS IN A COMPOUND HETEROZYGOUS PATIENT WITH PROTEIN-S DEFICIENCY

Genetic analysis revealed two distinct novel splice site mutations in a compound heterozygous patient with protein S deficiency. The paterna l mutation was a G-to-T transition at position -1 of the acceptor spli ce site, of intron N (Mutation I), and the maternal mutation was a G-t o-C transversion at position -1 of the donor splice site of intron C ( Mutation II). Both splice site mutations decreased the mutated mRNA ac cumulation to the same extent, approximately 40% of the normal mRNA. H owever, the mutations were associated with different phenotypical expr essions: the paternal mutant protein S was not detected in vivo, while the maternal mutant protein S was present in the plasma in reduced qu antity. Because Mutation I caused a cryptic splicing in the mutated mR NA, resulting in a reading frameshift and premature termination, the p redicted mutant protein S might be highly unstable. In contrast, Mutat ion II led to the substitution of Val46 by Leu, which might be much le ss deleterious for the synthesis, secretion and stability of the predi cted mutant protein S. It was supposed that the different post-transla tional metabolisms produced the distinct phenotypical expressions of t he mutations.