Human Molecular Genetics Advance Access originally published online on January 2, 2007
Human Molecular Genetics 2007 16(2):210-222; doi:10.1093/hmg/ddl470
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Long-range conserved non-coding SHOX sequences regulate expression in developing chicken limb and are associated with short stature phenotypes in human patients
1 Department of Molecular Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany, 2 Division of Cell and Developmental Biology, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, 3 Gemeinschaftspraxis, Friedrichstrasse 38–40, 01067 Dresden, Germany, 4 Institute of Clinical Genetics, Klinikum Stuttgart, Bismarckstrasse 3, 70176 Stuttgart, Germany, 5 Zentrum für Kinderheilkunde, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany and 6 Department of Paediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
* To whom correspondence should be addressed. Tel: +49 6221565059; Fax: +49 6221568884; Email: gudrun_rappold{at}med.uni-heidelberg.de
Received November 13, 2006; Accepted December 13, 2006
Defects in long-range regulatory elements have recently emerged as previously underestimated factors in the genesis of human congenital disorders. Léri-Weill dyschondrosteosis is a dominant skeletal malformation syndrome caused by mutations in the short stature homeobox gene SHOX. We have analysed four families with Léri-Weill dyschondrosteosis with deletions in the pseudoautosomal region but still with an intact SHOX coding region. Using fluorescence in situ hybridization and single nucleotide polymorphism studies, we identified an interval of 
200 kb that was deleted in all tested affected family members but retained in the unaffected members and in 100 control individuals. Comparative genomic analysis of this interval revealed eight highly conserved non-genic elements between 48 and 215 kb downstream of the SHOX gene. As mice do not have a Shox gene, we analysed the enhancer potential in chicken embryos using a green fluorescent protein reporter construct driven by the ß-globin promoter, by in ovo electroporation of the limb bud. We observed cis-regulatory activity in three of the eight non-genic elements in the developing limbs arguing for an extensive control region of this gene. These findings are consistent with the idea that the deleted region in the affected families contains several distinct elements that regulate Shox expression in the developing limb. Furthermore, the deletion of these elements in humans generates a phenotype apparently undistinguishable to those patients identified with mutations in the SHOX coding region and, for the first time, demonstrates the potential of an in vivo assay in chicken to monitor putative enhancer activity in relation to human disease.
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