Uniparental disomy causes deficiencies of vitamin K-dependent proteins

Autores de IIS La Fe

• María De Los Ángeles Dasi Carpio

  Autor

• Sara Izquierdo Sebastiá

  Autor

• Jose Diego Padilla Alarcon

  Autor

• Bienvenida Argiles Aparicio

  Autor

• Victor Vicente Vilas

  Autor

• Jaime Corral Peñafiel

  Autor

Participantes ajenos a IIS La Fe

• Gonzalez-Conejero R
• Garcia JL
• Garcia-Barberá N
• de la Morena-Barrio ME
• Hernández-Sánchez JM
• Hernández-Rivas JM

Grupos

• Hemostasia, Trombosis, Arteriosclerosis y Biología vascular

  

  Investigador Principal

  Pilar Medina Badenes

Abstract

Background: Inherited deficiency of all vitamin K-dependent coagulant factors (VKCFD) is a rare autosomal recessive disorder caused by mutations in the c-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 (D2GGCX). D2GGCX might be responsible for two unexpected clinical observations in the patient: (i) increased plasma osteocalcin levels following vitamin K-1 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 Delta 2GGCX 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.

Keywords

• alternative splicing; gamma-glutamyl carboxylase; uniparental disomy; vitamin K; VKCFD1