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

Int J Mol Sci. 2017 Jan 25;18(2):240. doi: 10.3390/ijms18020240.


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.

Keywords: GGCX; VKCFD1; cutis laxa; elastic fibers; gamma-carboxylation; pseudoxanthoma elasticum.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Blood Coagulation Disorders, Inherited / diagnosis
  • Blood Coagulation Disorders, Inherited / genetics
  • Carbon-Carbon Ligases / chemistry
  • Carbon-Carbon Ligases / genetics*
  • Carbon-Carbon Ligases / metabolism*
  • Congenital Abnormalities / diagnosis
  • Congenital Abnormalities / genetics
  • Eye / pathology
  • Gene Knockout Techniques
  • Genetic Association Studies*
  • Genetic Counseling
  • Genetic Predisposition to Disease
  • Genotype*
  • Humans
  • Mutation
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Protein Interaction Domains and Motifs
  • Skin / metabolism
  • Skin / pathology
  • Vitamin K / metabolism


  • Vitamin K
  • Carbon-Carbon Ligases
  • glutamyl carboxylase

Supplementary concepts

  • Vitamin K-Dependent Clotting Factors, Combined Deficiency Of, 1