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

Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recess ive osteochondrodysplasia that occurs in approximately two of every one mil lion people(1). This progressive skeletal disorder which manifests in child hood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications(2-4). Distinctiv e radiological signs are platyspondyly with hump-shaped central and posteri or portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia. The latter usually leads to premature secondary osteoarthritis often requi ring hip arthroplasty(3-5), Obligate female carriers are generally clinical ly 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). H ere we confirm and refine this localization to an interval of less than 170 kb by critical recombination events at DXS16 and AFMa124wc1 in two familie s. 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 tis sues including fetal cartilage. SEDL encodes a 140 amino acid protein with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport.