title: The molecular basis of X-linked spondyloepiphyseal dysplasia tarda.
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.
authors.affiliation: Centre for Medical Genetics, Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, and University of Adelaide Department of Paediatrics, Adelaide, Australia. agi.gedeon@adelaide.edu.au
authors.forename: A K
authors.initials: AK
authors.lastname: Gedeon
authors.forename: G E
authors.initials: GE
authors.lastname: Tiller
authors.forename: M
authors.initials: M
authors.lastname: Le Merrer
authors.forename: S
authors.initials: S
authors.lastname: Heuertz
authors.forename: L
authors.initials: L
authors.lastname: Tranebjaerg
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
authors.forename: S
authors.initials: S
authors.lastname: Robertson
authors.forename: I A
authors.initials: IA
authors.lastname: Glass
authors.forename: R
authors.initials: R
authors.lastname: Savarirayan
authors.forename: W G
authors.initials: WG
authors.lastname: Cole
authors.forename: D L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: B G
authors.initials: BG
authors.lastname: Kousseff
authors.forename: H
authors.initials: H
authors.lastname: Ohashi
authors.forename: B
authors.initials: B
authors.lastname: Zabel
authors.forename: A
authors.initials: A
authors.lastname: Munnich
authors.forename: J
authors.initials: J
authors.lastname: Gecz
authors.forename: J C
authors.initials: JC
authors.lastname: Mulley
mesh_terms: D001483:Base Sequence; D001827:Body Height / Q000235:genetics; D001846:Bone Development / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics; D005091:Exons / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D044469:Racial Groups / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D014960:X Chromosome / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D005819:Genetic Markers; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C120759:TRAPPC2 protein, human; D014157:Transcription Factors