Factor X Deficiency with Heterozygous Mutations of Novel p.G435S and Known p.G244R in a Patient Presenting with Severe Umbilical Hemorrhage.

ABSTRACT

A 10-day-old male patient was referred to our hospital with severe umbilical bleeding. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were prominently prolonged. Plasma coagulation factor X (FX) activity and antigen levels were 1% and 0.6%, respectively. A DNA sequence analysis of his leukocytes revealed a compound heterozygous state; known Gly244 to Arg (p.G244R) in exon 6 and a novel mutation of Gly 435 to Ser (p.G435S) in exon 8. A pedigree analysis showed that p.G244R originated from the paternal side, while p.G435S was from the maternal side. A p.G244R mutation was reported previously as FXDebrecen and this mutated protein was synthesized as a non-secretable protein. The glycine at amino acid position 435 in the C-terminal region is completely conserved in the trypsin-like serine protease family, including thrombin, FVII, protein C, plasmin, trypsin, and chymotrypsin. In a three-dimensional structural model of FX, Gly 435 was located within the 11th ß-strand and buried in the back of the catalytic pocket. Therefore, the substitution to serine was expected to disrupt this structure. p.G435S FX was also predicted to be synthesized and exist in the cytoplasm, but not to be secreted into culture media by a cDNA expression assay. These two mutations may be responsible for the type 1 (null levels of both activity and antigen in plasma) FX deficiency with severe bleeding phenotype.