Human Molecular Genetics Advance Access published online on July 29, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg248
© 2003 by Oxford University Press
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1 Cell & Molecular Genetics, MRC Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, UK
* To whom correspondence should be addressed. E-mail: david.fitzpatrick{at}hgu.mrc.ac.uk.
Cytogenetic evidence, in the form of deletions and balanced translocations, points to the existence of a locus on 2q32-q33, for which haploinsufficiency results in isolated cleft palate (CPO). Here we show by high resolution FISH mapping of two de novo CPO-associated translocations involving 2q32-q33 that one breakpoint interrupts the transcription unit of the gene encoding the DNA-binding protein SATB2 (formerly KIAA1034). The breakpoint in the other translocation is located 130 kb 3' to the SATB2 polyadenylation signal, within a conserved region of non-coding DNA. The SATB2 gene is transcribed in a telomeric to centromeric direction and lies in a gene-poor region of 2q32-q33; the nearest confirmed gene is 1.26 Mb centromeric to the SATB2 polyadenylation signal. SATB2-encoding transcripts are assembled from 11 exons that span 191 kb of genomic DNA. They encode a protein of 733 amino-acids that has two CUT domains and a homeodomain and shows a remarkable degree of evolutionary conservation, with only 3 amino acid substitutions between mouse and human. This protein belongs to the same family as SATB1, a nuclear matrix-attachment region binding protein implicated in transcriptional control and control of chromatin remodelling. There are also sequence similarities to the Drosophila protein DVE. Whole mount in situ hybridisation to mouse embryos shows site- and stage-specific expression of SATB2 in the developing palate. Despite the strong evidence supporting an important role for SATB2 in palate development, mutation analysis of 70 unrelated patients with CPO did not reveal any coding region variants. Key Words:
Cleft palate, de novo reciprocal translocations, chromatin remodelling
Article
Identification of SATB2 as the cleft palate gene on 2q32-q33
2 Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St James's University Hospital, Leeds LS9 7TF, UK
3 Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
4 Cell & Molecular Genetics, MRC Human Genetics Unit, Edinburgh, UK
5 Department of Clinical Genetics, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK
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