VKCFD2 – from clinical phenotype to molecular mechanism

Abstract

SummaryVitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) is an enzyme essential for the vitamin K cycle. VKORC1 catalyses the reduction of vitamin K 2,3-epoxide to the quinone form of vitamin K and further to vitamin K hydroquinone. The generated vitamin K hydroquinone serves as substrate for the enzyme γ-glutamyl-carboxylase which modifies all vitamin K-dependent proteins, allowing them to bind calcium ions necessary for physiological activity. Vitamin K-dependent proteins include the coagulation factors FII, FVII, FIX, FX, and proteins C, S und Z. Insufficient VKORC1 enzyme activity results in deficiency of the vitamin K-dependent clotting factors leading to haemorrhagic disorders. This phenotype is known as vitamin K clotting factor deficiency type 2 (VKCFD2). Worldwide, only four families of independent origin have been reported with this rare bleeding disorder. Affected family members carry the mutation VKORC1:p.Arg98Trp in homozygous form, the only mutation found so far to be associated with VKCFD2. Now, ten years after the identification of the VKORC1 gene, the molecular pathomechanism of VKCFD2 has been clarified. The Arg98Trp mutation disrupts an ER retention motif of VKORC1 leading to mislocalisation of the protein to outside the endoplasmatic reticulum. In this review, we summarize the clinical data, diagnosis, therapy and molecular patho -mechanism of VKCFD2.

Insights into the Molecular Genetic of Hemophilia A and Hemophilia B: The Relevance of Genetic Testing in Routine Clinical Practice

“…Sporadic cases of multiple vitamin K–dependent coagulation factor deficiency (VKCFDs) involving prothrombin, FVII, FIX, and FX might be misdiagnosed as HB. 41 Pathogenic HA/HB variants outside the region of the F8/F9 genes might remain undetectable with the current testing procedures. Although additional molecular and informatics research is needed, NGS is expected to elucidate cases without “detected” genetic alterations in the F8/F9 genes, leading to better understanding of genotype/phenotype correlation and more effective clinical care.…”