title: Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region.
abstract: Split-hand/split-foot malformation (SHFM, also called ectrodactyly) is a clinically variable and genetically heterogeneous group of limb malformations. Several SHFM loci have been mapped, including SHFM1 (7q21), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27) and SHFM5 (2q31). To date, mutations in a gene (TP63) have only been identified for SHFM4. SHFM3 has been shown by pulsed-field gel electrophoresis to be caused by an approximately 500 kb DNA rearrangement at 10q24. This region contains a number of candidate genes for SHFM3, though which gene(s) is (are) involved in the pathogenesis of SHFM3 is not known. Our aim in this study was to improve the diagnosis of SHFM3, and to begin to understand which genes are involved in SHFM3. Here we show, using two different techniques, FISH and quantitative PCR that SHFM3 is caused by a minimal 325 kb duplication containing only two genes (BTRC and POLL). The data presented provide improved methods for diagnosis and begin to elucidate the pathogenic mechanism of SHFM3. Expression analysis of 13 candidate genes within and flanking the duplicated region shows that BTRC (present in three copies) and SUFU (present in two copies) are overexpressed in SHFM3 patients compared to controls. Our data suggest that SHFM3 may be caused by overexpression of BTRC and SUFU, both of which are involved in beta-catenin signalling.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel-Servet, 1211 Geneva, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.forename: Uppala
authors.initials: U
authors.lastname: Radhakrishna
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Blouin
authors.forename: Sarantis
authors.initials: S
authors.lastname: Gagos
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.forename: Corinne
authors.initials: C
authors.lastname: Gehrig
authors.forename: Celia
authors.initials: C
authors.lastname: Delozier-Blanchet
authors.forename: Jitendra V
authors.initials: JV
authors.lastname: Solanki
authors.forename: Uday C
authors.initials: UC
authors.lastname: Patel
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
authors.forename: Fiorella
authors.initials: F
authors.lastname: Gurrieri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Neri
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics*; D005260:Female; D005532:Foot Deformities, Congenital / Q000453:epidemiology / Q000235:genetics*; D020440:Gene Duplication; D006228:Hand Deformities, Congenital / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D007194:India / Q000453:epidemiology; D008297:Male; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods*; D012097:Repressor Proteins / Q000235:genetics; D013557:Switzerland / Q000453:epidemiology; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics
chemical_list: C471644:BTRC protein, human; D044783:F-Box Proteins; C120449:FBXW4 protein, human; D012097:Repressor Proteins; C490764:SUFU protein, human; D044844:beta-Transducin Repeat-Containing Proteins