VKCFD2 – from clinical phenotype to molecular mechanism

Summary

Vitamin 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.

Zusammenfassung

Die Vitamin-K-2,3-Epoxid-Reduktase, Untereinheit 1 (VKORC1) ist ein Enzym, welches essenziell für den Vitamin-K-Zyklus ist. Sie katalysiert die Reduktion von Vitamin-K-2,3-Epoxid zum Vitamin-K-Chinon und weiter zum Vitamin-K-Hydrochinon. Das Vitamin-K-Hydrochinon dient der γ-Glutamyl-Carboxylase als Substrat für die Modifizierung VitaminK-abhängiger Proteine. Dadurch können diese Kalziumionen binden und erhalten somit ihre physiologische Aktivität. Zu den VitaminK-abhängigen Gerinnungsproteinen zählen FII, FVII, FIX, FX sowie die Proteine C, S und Z. Eine insuffiziente VKORC1 führt unter anderem zu einem Mangel aller Vitamin-K-abhängiger Gerinnungsfaktoren und somit zu einer Blutungsneigung. Dieser Phänotyp wird als VKCFD2 (vitamin K clotting factor deficiency type 2) bezeichnet. Weltweit wurden bisher vier Familien unabhängigen Ursprungs mit dieser seltenen Gerinnungsstörung diagnostiziert. Die betroffenen Familienmitglieder zeigen die Mutation VKORC: p.Arg98Trp in homo zygoter Ausprägung, welche die einzig bekannte Mutation ist, die zu einer VKCFD2 führt. Zehn Jahre nach der Identifikation des VKORC1-Gens wurde jetzt der molekulare Pathomechanismus der VKCFD2 aufgeklärt. Die Arg98Trp-Mutation führt zur Zerstörung eines ER-Retentionsmotivs der VKORC1 und damit zur Fehllokalisation des Proteins außerhalb des endoplasmatischen Retikulums. Diese Übersichtsarbeit fasst die klinischen Symptome, die Diagnostik, Behandlung und den molekularen Pathomechanismus der VKCFD2 zusammen.

Keywords

VKCFD2 - VKOR - VKORC1 - vitamin K - mutation

Schlüsselwörter

VKCFD2 - VKOR - VKORC1 - Vitamin K - Mutation

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