title: Characterization of two ectrodactyly-associated translocation breakpoints separated by 2.5 Mb on chromosome 2q14.1-q14.2.
abstract: Split hand-split foot malformation or ectrodactyly is a heterogeneous congenital defect of digit formation. The aim of this study is the mapping of the breakpoints and a detailed molecular characterization of the candidate genes for an isolated and syndromic form of ectrodactyly, both associated with de novo apparently balanced chromosome translocations involving the same chromosome 2 band, [t(2;11)(q14.2;q14.2)] and [t(2;4)(q14.1;q35)], respectively. Breakpoints were mapped by fluorescence in situ hybridization using bacterial artificial chromosome clones. Where possible, these breakpoints were further delimited. Candidate genes were screened for pathogenic mutations and the expression levels of two of them analysed. The isolated bilateral split foot malformation-associated chromosome 2 breakpoint was localized at 120.9 Mb, between the two main candidate genes, encoding GLI-Kruppel family member GLI2 and inhibin-betaB. The second breakpoint associated with holoprosencephaly, hypertelorism and ectrodactyly syndrome was mapped 2.5 Mb proximal at 118.4 Mb and the candidate genes identified from this region were the insulin-induced protein 2 and the homeobox protein engrailed-1. No clear pathogenic mutations were identified in any of these genes. The breakpoint between INHBB and GLI2 coincides with a previously identified translocation breakpoint associated with ectrodactyly. We propose a mechanism by which translocations in the 2q14.1-q14.2 region disrupt the specific arrangement of long-range regulatory elements that control the tight quantitative spatiotemporal expression of one or more genes from the breakpoint region.
authors.affiliation: Department of Genetics, National Institute of Health Dr Ricardo Jorge, Lisboa, Portugal. dezso.david@insa.min-saude.pt
authors.forename: Dezso
authors.initials: D
authors.lastname: David
authors.forename: Bárbara
authors.initials: B
authors.lastname: Marques
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferreira
authors.forename: Paula
authors.initials: P
authors.lastname: Vieira
authors.forename: Alfredo
authors.initials: A
authors.lastname: Corona-Rivera
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Ferreira
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002889:Chromosomes, Human, Pair 2; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D028322:Inhibin-beta Subunits / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011247:Pregnancy; D014178:Translocation, Genetic; D000075746:Zinc Finger Protein Gli2
chemical_list: C513076:EN1 protein, human; C082593:GLI2 protein, human; D018398:Homeodomain Proteins; C422402:INHBB protein, human; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D000075746:Zinc Finger Protein Gli2; D028322:Inhibin-beta Subunits