title: The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly.
abstract: Molecular analysis of the reciprocal chromosomal translocation t(12;22)(p11.2;q13.3) cosegregating with a complex type of synpolydactyly showed involvement of an alternatively spliced exon of the fibulin-1 gene (FBLN1 located in 22q13.3) and the C12orf2 (HoJ-1) gene on the short arm of chromosome 12. Investigation of the possible functional involvement of the fibulin-1 protein (FBLN1) in the observed phenotype showed that FBLN1 is expressed in the extracellular matrix (ECM) in association with the digits in the developing limb. Furthermore, fibroblasts derived from patients with the complex type of synpolydactyly displayed alterations in the level of FBLN1-D splice variant incorporated into the ECM and secreted into the conditioned culture medium. By contrast, the expression of the FBLN1-C splice variant was not perturbed in the patient fibroblasts. Based on these findings, we propose that the t(12;22) results in haploinsufficiency of the FBLN1-D variant, which could lead to the observed limb malformations.
authors.affiliation: Centre for Human Genetics, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Debeer
authors.forename: E F P M
authors.initials: EF
authors.lastname: Schoenmakers
authors.forename: W O
authors.initials: WO
authors.lastname: Twal
authors.forename: W S
authors.initials: WS
authors.lastname: Argraves
authors.forename: L
authors.initials: L
authors.lastname: De Smet
authors.forename: J P
authors.initials: JP
authors.lastname: Fryns
authors.forename: W J M
authors.initials: WJ
authors.lastname: Van De Ven
mesh_terms: D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005347:Fibroblasts; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D017689:Polydactyly / Q000209:etiology / Q000235:genetics*; D013576:Syndactyly / Q000209:etiology / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C060820:fibulin