Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/28108
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Type: Journal article
Title: The molecular basis of X-linked spondyloepiphyseal dysplasia tarda
Author: Gedeon, A.
Tiller, G.
Le Merrer, M.
Heuertz, S.
Tranebjaerg, L.
Chitayat, D.
Robertson, S.
Glass, I.
Savarirayan, R.
Cole, W.
Rimoin, D.
Kousseff, B.
Ohashi, H.
Zabel, B.
Munnich, A.
Gecz, J.
Mulley, J.
Citation: American Journal of Human Genetics, 2001; 68(6):1386-1397
Publisher: University of Chicago Press
Issue Date: 2001
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
A.K. Gedeon, G.E. Tiller, M. Le Merrer, S. Heuertz, L. Tranebjaerg, D. Chitayat, S. Robertson, I.A. Glass, R. Savarirayan, W.G. Cole, D.L. Rimoin, B.G. Kousseff, H. Ohashi, B. Zabel, A. Munnich, J. Gecz and J.C. Mulley
Abstract: The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2-7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G-->A, 157-158delAT, 191-192delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.
Keywords: X Chromosome; Humans; Osteochondrodysplasias; Carrier Proteins; Membrane Transport Proteins; Transcription Factors; RNA, Messenger; Genetic Markers; Body Height; Reverse Transcriptase Polymerase Chain Reaction; DNA Mutational Analysis; Base Sequence; Structure-Activity Relationship; Bone Development; Haplotypes; Phenotype; Mutation; Polymorphism, Genetic; Exons; Molecular Sequence Data; Continental Population Groups; Ethnic Groups; Male; Genetic Testing; Genetic Linkage
Rights: © 2001 by The American Society of Human Genetics
RMID: 0020010882
DOI: 10.1086/320592
Appears in Collections:Molecular and Biomedical Science publications

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