HOMOZYGOSITY FOR A NOVEL MISSENSE MUTATION IN THE PROTHROMBIN GENE CAUSING A SEVERE BLEEDING DISORDER

A patient with a severe bleeding tendency and hypoprothrombinemia (Fac tor II activity 2%, Factor lI antigen 5%) was screened for the presenc e of alterations in his prothrombin gene, Direct sequencing of PCR fra gments derived from the coding and flanking regions of the prothrombin gene, revealed that the patient was homozygous for an A --> G substit ution in exon 3, This substitution predicts the replacement of Tyr 44 (TAG) by Cys (TGC) in the prothrombin molecule. Both parents were foun d to be heterozygous for the same mutation. Further family studies rev ealed complete cosegregation of the mutation with the prothrombin defi ciency. Only the five homozygous brothers and sisters of the propositu s were clinically affected (severe hemorrhages including epistaxis, so ft tissue, muscle and joint bleedings in all, and severe hemorrhages i n the two women). The bleeding tendency therefore seems to inherit as an autosomal recessive