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UNIPARENTAL DISOMY: A NEW MECHANISM CAUSING DEFICIENCY OF VITAMIN K-DEPENDENT PROTEINS
Autores:
ROCÍO GONZÁLEZ-CONEJERO HILLA
, M ANGELES DASÍ, SARA IZQUIERDO, JOSE PADILLA,
NURIA GARCÍA BARBERÁ
, BIENVENIDA ARGILÉS, JUAN LUIS GARCIA, JESUS MARIA HERNANDEZ-RIVAS, JESUS MARIA HERNANDEZ-SANCHEZ,
MARÍA EUGENIA DE LA MORENA BARRIO
,
VICENTE VICENTE GARCÍA
,
JAVIER CORRAL DE LA CALLE
,
Grupos de investigación:
[GI/IMIB/C001/2011] HEMATOLOGÍA Y ONCOLOGÍA MÉDICA CLÍNICO-EXPERIMENTAL
Comunicación:
Antecedentes:
Inherited deficiency of all vitamin K-dependent coagulant factors (VKCFD) is a rare autosomal recessive disorder caused by mutations in g-glutamyl carboxylase (GGCX) or vitamin K-epoxide reductase (VKORC1) with great heterogeneity both in terms of clinical presentation and response to treatment.
Métodos:
A Caucasian infant with suspicion of VKCFD and his relatives were studied. Informed consent was obtained from all participants. Hemostatic VKD proteins and coagulation parameters were determined in an automated coagulometer. GLA-type osteocalcin and undercarboxylated osteocalcin were quantified by ELISA. The promoter region as well as the coding and flanking regions of both VKORC1 and GGCX were sequenced from genomic DNA. RT-PCR from whole RNA obtained from mononuclear cells of peripheral blood of healthy subjects, patient and family members was used for sequencing and quantification of GGCX isoforms. This study was also done in mRNA obtained from liver of 3 healthy subjects. qRT-PCR, which used ACTB as endogenous reference, was done with SYBR™ Green master mix. Quantification was done using the 2-?Ct method. DNA was also analyzed on the Affymetrix® CytoScan 750K Array. Data analysis was performed using the Chromosome Analysis Suite. All markers were used to determine copy number and SNP probes were used to calculate loss of heterozygosity (LOH) and genotype calls. In addition, an Illumina® TruSight™ One sequencing panel on a MiSeq platform was used. Qubit® 2.0 Fluorometer system was used for the quantification of the DNA and the genomic library. For data analysis we used VariantStudio™ ver. 2.2.1 and Integrative Genomics Viewer software ver. 2.3.68.
Resultados:
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 messenger coding for the full length protein, and to a 4-fold overexpression of the smaller mRNA isoform lacking exon 2 (?2GGCX). ?2GGCX might be responsible for two unexpected clinical observations in the patient: 1) increased plasma osteocalcin levels following vitamin K1, and 2) a mild non-bleeding phenotype.
Conclusiones:
Our study identifies a new autosomic disease, VKCFD1, being caused by UPD. These data suggest that the ?2GGCX isoform may retain enzymatic activity, and strongly encourages evaluating both hepatic and non-hepatic vitamin K-dependent proteins to assess differing responses to vitamin K supplementation in VKCFD patients.
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