Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda

Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people 1 . This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications 2 , 3 , 4 . Distinctive radiological signs are platyspondyly with hump-shaped central and posterior portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia. The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty 3 , 4 , 5 . Obligate female carriers are generally clinically and radiographically indistinguishable from the general population 4 , 5 , although some cases have phenotypic changes consistent with expression of the gene defect 2 , 4 , 6 , 7 . The SEDL gene has been localized to Xp22 (Refs 8 , 9 ) in the approximately 2-Mb interval between DXS16 and DXS987 (ref. 10 ). Here we confirm and refine this localization to an interval of less than 170 kb by critical recombination events at DXS16 and AFMa124wc1 in two families. In one candidate gene we detected three dinucleotide deletions in three Australian families which effect frameshifts causing premature stop codons. The gene designated SEDL is transcribed as a 2.8-kb transcript in many tissues including fetal cartilage. SEDL encodes a 140 amino acid protein with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport.