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GGCX-associated phenotypes : an overview in search of genotype-phenotype correlations

Eva De Vilder (UGent) , Jens Debacker (UGent) and Olivier Vanakker (UGent)
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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 correlationsa frequent problem in orphan diseaseswe 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
gamma-carboxylation, GGCX, cutis laxa, pseudoxanthoma elasticum, VKCFD1, elastic fibers, GAMMA-GLUTAMYL-CARBOXYLASE, COAGULATION-FACTOR DEFICIENCY, K-DEPENDENT CARBOXYLASE, CONGENITAL COMBINED DEFICIENCY, GLA-RICH PROTEIN, PSEUDOXANTHOMA ELASTICUM, CUTIS LAXA, COMPOUND HETEROZYGOSITY, TRANSMEMBRANE DOMAIN, MASS-SPECTROMETRY

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MLA
De Vilder, Eva, Jens Debacker, and Olivier Vanakker. “GGCX-associated Phenotypes : an Overview in Search of Genotype-phenotype Correlations.” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 18.2 (2017): n. pag. Print.
APA
De Vilder, E., Debacker, J., & Vanakker, O. (2017). GGCX-associated phenotypes : an overview in search of genotype-phenotype correlations. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 18(2).
Chicago author-date
De Vilder, Eva, Jens Debacker, and Olivier Vanakker. 2017. “GGCX-associated Phenotypes : an Overview in Search of Genotype-phenotype Correlations.” International Journal of Molecular Sciences 18 (2).
Chicago author-date (all authors)
De Vilder, Eva, Jens Debacker, and Olivier Vanakker. 2017. “GGCX-associated Phenotypes : an Overview in Search of Genotype-phenotype Correlations.” International Journal of Molecular Sciences 18 (2).
Vancouver
1.
De Vilder E, Debacker J, Vanakker O. GGCX-associated phenotypes : an overview in search of genotype-phenotype correlations. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 2017;18(2).
IEEE
[1]
E. De Vilder, J. Debacker, and O. Vanakker, “GGCX-associated phenotypes : an overview in search of genotype-phenotype correlations,” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 18, no. 2, 2017.
@article{8510257,
  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 correlationsa frequent problem in orphan diseaseswe 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.},
  articleno    = {240},
  author       = {De Vilder, Eva and Debacker, Jens and Vanakker, Olivier},
  issn         = {1422-0067},
  journal      = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
  keywords     = {gamma-carboxylation,GGCX,cutis laxa,pseudoxanthoma elasticum,VKCFD1,elastic fibers,GAMMA-GLUTAMYL-CARBOXYLASE,COAGULATION-FACTOR DEFICIENCY,K-DEPENDENT CARBOXYLASE,CONGENITAL COMBINED DEFICIENCY,GLA-RICH PROTEIN,PSEUDOXANTHOMA ELASTICUM,CUTIS LAXA,COMPOUND HETEROZYGOSITY,TRANSMEMBRANE DOMAIN,MASS-SPECTROMETRY},
  language     = {eng},
  number       = {2},
  pages        = {34},
  title        = {GGCX-associated phenotypes : an overview in search of genotype-phenotype correlations},
  url          = {http://dx.doi.org/10.3390/ijms18020240},
  volume       = {18},
  year         = {2017},
}

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