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Uniparental disomy causes deficiencies of vitamin K-dependent proteins

AutorDasi, M. A.; Gonzalez-Conejero, R.; Izquierdo, S.; Padilla, Jose; García, Juan L. ; Garcia-Barberá, N.; Argilés, B.; Morena-Barrio, M. E. de la; Hernandez-Sánchez, Jesus M.; Hernández, Jesús M. ; Vicente, Vicente; Corral, J.
Palabras claveVKCFD1
Vitamin K
Alternative splicing
Uniparental disomy
γ-glutamyl carboxylase
Fecha de publicación2016
EditorJohn Wiley & Sons
International Society on Thrombosis and Haemostasis
CitaciónJournal of Thrombosis and Haemostasis 14(12): 2410-2418 (2016)
ResumenEssentials Vitamin K-dependent coagulant factor deficiency (VKCFD) is a rare autosomal recessive disorder. We describe a case of inherited VKCFD due to uniparental disomy. The homozygous mutation caused the absence of GGCX isoform 1 and overexpression of Δ2GGCX. Hepatic and non-hepatic vitamin K-dependent proteins must be assayed to monitor VKCFD treatment. Summary: Background Inherited deficiency of all vitamin K-dependent coagulant factors (VKCFD) is a rare autosomal recessive disorder caused by mutations in the γ-glutamyl carboxylase gene (GGCX) or the vitamin K epoxide reductase gene (VKORC1), with great heterogeneity in terms of both clinical presentation and response to treatment. Objective To characterize the molecular basis of VKCFD in a Spanish family. Methods and Results Sequencing of candidate genes, comparative genomic hybridization and massive sequencing identified a new mechanism causing VKCFD in the proband. Uniparental disomy (UPD) of chromosome 2 caused homozygosity of a mutation (c.44-1G>A) resulting in aberrant GGCX splicing. This change contributed to absent expression of the mRNA coding for the full-length protein, and to four-fold overexpression of the smaller mRNA isoform lacking exon 2 (Δ2GGCX). Δ2GGCX might be responsible for two unexpected clinical observations in the patient: (i) increased plasma osteocalcin levels following vitamin K supplementation; and (ii) a mild non-bleeding phenotype. Conclusions Our study identifies a new autosomal disease, VKCFD1, caused by UPD. These data suggest that the Δ2GGCX isoform may retain enzymatic activity, and strongly encourage the evaluation of both hepatic and non-hepatic vitamin K-dependent proteins to assess differing responses to vitamin K supplementation in VKCFD patients.
URIhttp://hdl.handle.net/10261/168780
Identificadoresdoi: 10.1111/jth.13517
e-issn: 1538-7836
issn: 1538-7933
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