title: 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 encodingGGCXgene 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 oneGGCXmutation 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.
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium. eva.devilder@ugent.be.
authors.forename: Eva Y G
authors.initials: EY
authors.lastname: De Vilder
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium. jensm.debacker@ugent.be.
authors.forename: Jens
authors.initials: J
authors.lastname: Debacker
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium. olivier.vanakker@ugent.be.
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Vanakker
mesh_terms: D025861:Blood Coagulation Disorders, Inherited / Q000175:diagnosis / Q000235:genetics; D019735:Carbon-Carbon Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics; D005123:Eye / Q000473:pathology; D055786:Gene Knockout Techniques; D056726:Genetic Association Studies; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014812:Vitamin K / Q000378:metabolism
chemical_list: D014812:Vitamin K; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase
keywords: GGCX; VKCFD1; cutis laxa; elastic fibers; gamma-carboxylation; pseudoxanthoma elasticum