GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations

Abstract

Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.

Vitamin K2-Dependent GGCX and MGP Are Required for Homeostatic Calcium Regulation of Sperm Maturation

“…To extend our rat study on VKD proteins to human reproductive health, we identified a significant difference in the GGCX SNP mutation rs699664 in the asthenozoospermic samples compared with controls, but we found no differences in MGP. It is known that the GGCX rs699664 SNP mutation results in the amino acid change from 325Arg to Gln in GGCX (De Vilder et al., 2017) and is associated with bone density in elderly women (Kinoshita et al., 2007, Rieder et al., 2007). Asthenozoospermia is considered a common cause of male infertility characterized by a reduction in both sperm motility and normal sperm morphology (Sanchez-Alvarez et al., 2012).…”

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

“…We next repeated the analysis using 812 IPAH cases only (all European) and observed significant associations for BMPR2 (p=1.0E-7, FDR=9.0E-04), KLK1 (p=1.0E-7, FDR=9.0E-04), GDF2 (p=3.0E-07, FDR=0.002) and GGCX (p=5.0E-07, FDR=0.002) ( Figure 4). GGCX encodes gamma-glutamyl carboxylase, implicated in coagulation factor deficiencies and ectopic mineralization of soft tissues 34 . These four genes were the only genes to reach genome-wide significance among IPAH cases.…”

Understanding the Clotting Cascade, Regulators, and Clinical Modulators of Coagulation

“…The vitamin K epoxide is recycled to reduced vitamin K by the vitamin K epoxide reductase (VKOR) enzyme complex [91,92]. GGCX is encoded by the gene located on chromosome 2 and VKORC1 is encoded by the gene present on chromosome 16 [93,94]. Mutations in these gene cause loss of GGCX or VKOR complex function and lead to vitamin K dependent coagulation factor deficiency [95].…”