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

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 whi...

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Autores principales: De Vilder, Eva Y. G., Debacker, Jens, Vanakker, Olivier M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343777/
https://www.ncbi.nlm.nih.gov/pubmed/28125048
http://dx.doi.org/10.3390/ijms18020240
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author De Vilder, Eva Y. G.
Debacker, Jens
Vanakker, Olivier M.
author_facet De Vilder, Eva Y. G.
Debacker, Jens
Vanakker, Olivier M.
author_sort De Vilder, Eva Y. G.
collection PubMed
description 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.
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spelling pubmed-53437772017-03-16 GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations De Vilder, Eva Y. G. Debacker, Jens Vanakker, Olivier M. Int J Mol Sci Review 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. MDPI 2017-01-25 /pmc/articles/PMC5343777/ /pubmed/28125048 http://dx.doi.org/10.3390/ijms18020240 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
De Vilder, Eva Y. G.
Debacker, Jens
Vanakker, Olivier M.
GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations
title GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations
title_full GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations
title_fullStr GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations
title_full_unstemmed GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations
title_short GGCX-Associated Phenotypes: An Overview in Search of Genotype-Phenotype Correlations
title_sort ggcx-associated phenotypes: an overview in search of genotype-phenotype correlations
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343777/
https://www.ncbi.nlm.nih.gov/pubmed/28125048
http://dx.doi.org/10.3390/ijms18020240
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