The molecular basis of X-linked spondyloepiphyseal dysplasia tarda

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologi cally 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 unr elated cases of X-linked SEDL ascertained from different ethnic populations . Twenty-one different disease-associated mutations now have been identifie d 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 erro r due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >4 3% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleoti de deletions. Altogether, deletions account for 57% (17/30) of all known SE DL mutations. Four recurrent mutations (IVS3+5G -->A, 157-158delAT, 191-192 delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases . The results of haplotype analyses and the diverse ethnic origins of patie nts support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the ot her relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the com plete unaltered SEDL-gene product is essential for normal bone growth. Mole cular diagnosis can now be offered for presymptomatic testing of this disor der. Appropriate lifestyle decisions and, eventually, perhaps, specific SED L therapies may ameliorate the prognosis of premature osteoarthritis and th e need for hip arthroplasty.