Failure in the detection of aberrant mRNA from the heterozygotic splice site mutant allele for protein S in a patient with protein S deficiency

A 29-year-old male patient with acute arterial obstruction and a medical hi story including thrombosis in the deep veins and pulmonary infarction prese nted with a reduced level of both protein S (PS) activity and free PS. Sequ encing of the genomic PS gene in this patient revealed that the patient was heterozygous for the mutant PS allele, in which a nucleotide substitution occurred at the donor splice site in intron 12 (GT to GA). The patient was heterozygous for PS genes having dimorphic codons for Pro626 (CCA/CCG) and the aberrant allele in this patient was associated with the CCA form. Allel ic exclusion of PS expression was demonstrated by use of Pro626 (CCA/CCG) d imorphism and only a normal mRNA sequence derived from the CCG-allele was i dentified in the patient. These findings suggested that the mutation at the splice site in the PS gene caused either defective production of mRNA or t he gene may have produced extremely unstable RNA products, leading to reduc ed levels of PS activity and free PS in this patient. (C) 2001 Elsevier Sci ence Ltd. All rights reserved.