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  A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome

Klopocki, E., Ott, C.-E., Benatar, N., Ullmann, R., Mundlos, S., & Lehmann, K. (2008). A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. Journal of Medical Gentics, 45(6), 370-375. doi:10.1136/jmg.2007.055699.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-809A-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-809B-F
Genre: Journal Article
Alternative Title : J Med Genet

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Klopocki, E.1, Author              
Ott, C-E, Author
Benatar, N, Author
Ullmann, Reinhardt2, Author              
Mundlos, Stefan1, Author              
Lehmann, Katarina, Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479645              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2008-01-04
 Publication Status: Published in print
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Title: Journal of Medical Gentics
  Alternative Title : J Med Genet
Source Genre: Journal
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Pages: - Volume / Issue: 45 (6) Sequence Number: - Start / End Page: 370 - 375 Identifier: ISSN: 0022-2593