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Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia

Item Type:Article
Title:Deletion of long-range regulatory elements upstream of SOX9 causes campomelic dysplasia
Creators Name:Wunderle, V.M. and Critcher, R. and Hastie, N. and Goodfellow, P.N. and Schedl, A.
Abstract:Campomelic dysplasia (CD) is a rare, neonatal human chondrodysplasia characterized by bowing of the long bones and often associated with male-to-female sex-reversal. Patients present with either heterozygous mutations in the SOX9 gene or chromosome rearrangements mapping at least 50 kb upstream of SOX9. Whereas mutations in SOX9 ORF cause haploinsufficiency, the effects of translocations 5' to SOX9 are unclear. To test whether these rearrangements also cause haploinsufficiency by altering spatial and temporal expression of SOX9, we generated mice transgenic for human SOX9-lacZ yeast artificial chromosomes containing variable amounts of DNA sequences upstream of SOX9. We show that elements necessary for SOX9 expression during skeletal development are highly conserved between mouse and human and reveal that a rearrangement upstream of SOX9, similar to those observed in CD patients, leads to a substantial reduction of SOX9 expression, particularly in chondrogenic tissues. These data demonstrate that important regulatory elements are scattered over a large region upstream of SOX9 and explain how particular aspects of the CD phenotype are caused by chromosomal rearrangements 5' to SOX9.
Keywords:Base Sequence, DNA Primers, High Mobility Group Proteins, Nucleic Acid Regulatory Sequences, Osteochondrodysplasias, Sequence Deletion, Sequence Tagged Sites, SOX9 Transcription Factor, Transcription Factors, Transgenes, Yeast Artificial Chromosomes, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:95
Number:18
Page Range:10649-10654
Date:1 September 1998
Official Publication:http://www.pnas.org/content/95/18/10649.abstract
PubMed:View item in PubMed

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