Factor V (FV) deficiency is a rare autosomal recessive haemorrhagic disorder associated with moderate to severe bleeding symptoms. Conventional mutational screening leads to a complete molecular genetic diagnosis only in about 80-90% of cases. Large gene rearrangements, which could explain at least part of the "missing alleles" have not been reported so far in FV-deficient patients. In this work, we investigated a family with hereditary FV deficiency, in which the proband is compound heterozygous for a 205-Kb deletion, involving the first seven exons of F5, and the entire selectin P, L, and E genes, and for a novel splicing mutation (IVS12+5G>A). The deletion breakpoints, determined by using a combination of semi-quantitative real-time PCR and long PCR assays, occurred within AluY repeat sequences, suggesting an Alu-mediated unequal homologous recombination as the mechanism responsible for the deletion. The in vitro characterisation of the IVS12+5G>A mutation demonstrated that this mutation causes the skipping of exon 12 and the activation of a cryptic splice site. Low levels of residual wild-type splicing were also detectable, in agreement with the notion that the complete absence of FV may be not compatible with life. © Schattauer 2011.

Identification of the first alu-mediated large deletion involving the f5 gene in a compound heterozygous patient with severe factor v deficiency / I. Guella, E.M. Paraboschi, W.A. van Schalkwyk, R. Asselta, S. Duga. - In: THROMBOSIS AND HAEMOSTASIS. - ISSN 0340-6245. - 106:2(2011 Aug), pp. 296-303. [10.1160/TH11-03-0149]

Identification of the first alu-mediated large deletion involving the f5 gene in a compound heterozygous patient with severe factor v deficiency

I. Guella;E.M. Paraboschi;R. Asselta;S. Duga
2011-08

Abstract

Factor V (FV) deficiency is a rare autosomal recessive haemorrhagic disorder associated with moderate to severe bleeding symptoms. Conventional mutational screening leads to a complete molecular genetic diagnosis only in about 80-90% of cases. Large gene rearrangements, which could explain at least part of the "missing alleles" have not been reported so far in FV-deficient patients. In this work, we investigated a family with hereditary FV deficiency, in which the proband is compound heterozygous for a 205-Kb deletion, involving the first seven exons of F5, and the entire selectin P, L, and E genes, and for a novel splicing mutation (IVS12+5G>A). The deletion breakpoints, determined by using a combination of semi-quantitative real-time PCR and long PCR assays, occurred within AluY repeat sequences, suggesting an Alu-mediated unequal homologous recombination as the mechanism responsible for the deletion. The in vitro characterisation of the IVS12+5G>A mutation demonstrated that this mutation causes the skipping of exon 12 and the activation of a cryptic splice site. Low levels of residual wild-type splicing were also detectable, in agreement with the notion that the complete absence of FV may be not compatible with life. © Schattauer 2011.
Alu sequence; Coagulation factor V; Factor V deficiency; Large deletion; Splicing mutation
Settore BIO/11 - Biologia Molecolare
THROMBOSIS AND HAEMOSTASIS
http://www.schattauer.de/en/magazine/subject-areas/journals-a-z/thrombosis-and-haemostasis/issue/special/manuscript/16179/download.html
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/292206
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