title: A mutation in LMAN1 (ERGIC-53) causing combined factor V and factor VIII deficiency is prevalent in Jews originating from the island of Djerba in Tunisia.
abstract: Combined deficiency of factor V and factor VIII is a rare autosomal recessive bleeding disorder that is caused by mutations in the LMAN1 or MCFD2 genes. These genes encode for proteins that form a complex that takes part in the transport of factor V and factor VIII from the endoplasmic reticulum to Golgi. Two mutations in LMAN1 have been observed in Jews: a guanine (G) insertion in exon 1 among Middle Eastern Jewish families, and a thymidine (T) to cytosine (C) transition in intron 9 at a donor splice site among Tunisian families. For each mutation, haplotype analysis revealed a founder effect. Because all affected Tunisian families belong to an ancient Jewish community in the island of Djerba off the coast of Tunisia, we screened members of this community for the intron 9 T --> C transition. Among 233 apparently unrelated individuals five heterozygotes were detected, predicting an allele frequency of 0.0107 (95% confidence interval, 0.0035-0.0248), while among 259 North African Jews none was found to carry the mutation. The prevalence of the mutation in Djerba Jews is consistent with the observation that all affected Tunisian Jewish families have origins in Djerba and with the finding of a common haplotype for the 9 + 2 T --> C mutation. The G insertion in exon 1 was found in one of 245 Iraqi Jews, predicting an allele frequency of 0.0022 (95% confidence interval, 0.0001-0.0123), but in none of 180 Iranian Jews examined. In view of the relatively low frequency of the mutations in the respective populations it seems reasonable to advocate carrier detection and prenatal diagnosis only in affected families.
authors.affiliation: Thrombosis and Hemostasis Research Institute, Chaim Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Avichai
authors.initials: A
authors.lastname: Segal
authors.forename: Ariella
authors.initials: A
authors.lastname: Zivelin
authors.forename: Nurit
authors.initials: N
authors.lastname: Rosenberg
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.forename: Uri
authors.initials: U
authors.lastname: Seligsohn
mesh_terms: D005091:Exons / Q000235:genetics; D005165:Factor V / Q000378:metabolism*; D005169:Factor VIII / Q000378:metabolism*; D005787:Gene Frequency / Q000235:genetics; D006056:Golgi Apparatus / Q000378:metabolism; D006470:Hemorrhage / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007438:Introns / Q000235:genetics; D007585:Jews; D037241:Mannose-Binding Lectins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D014416:Tunisia
chemical_list: C084004:LMAN1 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D005165:Factor V; D005169:Factor VIII