Uniparental disomy causes deficiencies of vitamin K-dependent proteins.
Essentials 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.



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 K1supplementation; 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.
Unidad de Hematología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
M A
MA
Dasi
Centro Regional de Hemodonación, Universidad de Murcia-IMIB, Murcia, Spain.
R
R
Gonzalez-Conejero
Unidad de Hematología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
S
S
Izquierdo
Centro Regional de Hemodonación, Universidad de Murcia-IMIB, Murcia, Spain.
J
J
Padilla
Centro de Investigación del Cáncer-Universidad de Salamanca-CSIC, Salamanca, Spain.
J L
JL
Garcia
Centro Regional de Hemodonación, Universidad de Murcia-IMIB, Murcia, Spain.
N
N
Garcia-Barberá
Unidad de Hematología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
B
B
Argilés
Centro Regional de Hemodonación, Universidad de Murcia-IMIB, Murcia, Spain.|Grupo CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
M E
ME
de la Morena-Barrio
Centro de Investigación del Cáncer-Universidad de Salamanca-CSIC, Salamanca, Spain.
J M
JM
Hernández-Sánchez
Centro de Investigación del Cáncer-Universidad de Salamanca-CSIC, Salamanca, Spain.
J M
JM
Hernández-Rivas
Centro Regional de Hemodonación, Universidad de Murcia-IMIB, Murcia, Spain.|Grupo CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
V
V
Vicente
Centro Regional de Hemodonación, Universidad de Murcia-IMIB, Murcia, Spain.|Grupo CB15/00055 del Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
J
J
Corral
D001777:Blood Coagulation; D019735:Carbon-Carbon Ligases / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D006487:Hemostasis; D006720:Homozygote; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013030:Spain; D024182:Uniparental Disomy; D014812:Vitamin K / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases / Q000172:deficiency* / Q000235:genetics
D012333:RNA, Messenger; D014812:Vitamin K; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase
VKCFD1; alternative splicing; uniparental disomy; vitamin K; γ-glutamyl carboxylase