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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents



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ID: 410648.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome
Authors:Klopocki, E.; Ott, C-E; Benatar, N; Ullmann, Reinhardt; Mundlos, Stefan; Lehmann, Katarina
Language:English
Research Context:CLINICAL REPORT
Date of Publication (YYYY-MM-DD):2008-01-04
Title of Journal:Journal of Medical Gentics
Journal Abbrev.:J Med Genet
Volume:45
Issue / Number:6
Start Page:370
End Page:375
Copyright:© 2008 by the BMJ Publishing Group Ltd.
Review Status:not specified
Audience:Experts Only
Abstract / Description:BACKGROUND: Sonic hedgehog (SHH) plays an important role in defining the anterior-posterior axis in the developing limbs. A highly conserved non-coding sequence about approximately 1 Mb upstream from the sonic hedgehog gene (SHH) was shown to be a long range regulator for SHH expression in the limb bud. Point mutations within this non-coding regulatory region designated ZRS lead to ectopic expression of Shh in the anterior margin of the limb bud, as shown in mice, and cause the human triphalangeal thumb and polysyndactyly (TPT-PS) phenotype. Even though this association is well established, its molecular mechanism remains unclear. METHODS AND RESULTS: We investigated a large pedigree with variable TPT-PS. A single nucleotide exchange within the SHH limb regulator sequence was excluded, but locus specific microsatellite marker analyses confirmed a linkage to this region. Subsequently, array comparative genomic hybridisation (array CGH) was carried out using a submegabase whole human genome tiling path bacterial artificial chromosome (BAC) array revealing a microduplication in 7q36.3 in affected individuals. A duplicated region of 588,819 bp comprising the ZRS was identified by quantitative real-time polymerase chain reaction (qPCR) and direct sequencing. CONCLUSION: A novel microduplication in 7q36.3 results in a similar TPT-PS phenotype as caused by single nucleotide alterations in the ZRS, the limb specific SHH regulatory element. Duplications can be added to the growing list of mechanisms that cause abnormalities of long range transcriptional control.
Comment of the Author/Creator:Correspondence to:
Dr K Lehmann, Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; katarina.lehmann@charite.de
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Klinik für Handchirurgie und angeborene Handfehlbildungen, Krankenhaus Marienstift, Braunschweig, Germany.
Identifiers:URL:http://jmg.bmj.com/cgi/reprint/45/6/370
DOI:10.1136/jmg.2007.055699
ISSN:0022-2593
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