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

Abstract

Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people. 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. 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. Obligate female carriers are generally clinically and radiographically indistinguishable from the general population, although some cases have phenotypic changes consistent with expression of the gene defect. 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.

Crystal Structure of SEDL and Its Implications for a Genetic Disease Spondyloepiphyseal Dysplasia Tarda

“…Both transcripts from the two chromosomes are expressed in the affected tissue, epiphyseal cartilage, and also in most other tissues (17). A compensatory effect of SEDL originating from chromosome 19 could contribute to the absence of a phenotypic effect in most tissues of SEDT patients (12).…”

“…Trs20p, the SEDL orthologue in yeast, is also a component of yeast TRAPP I and TRAPP II. The identification of SEDL as the gene responsible for SEDT was unexpected, since different types of chondrodysplasias and skeletal dysplasias are accounted mostly by the genes encoding structural molecules of cartilage such as collagen and cartilage oligomeric matrix protein (12,16). A pseudogene of SEDL on human chromosome 19 was found to encode a protein identical to that of SEDL.…”

“…SEDT is caused by mutations in SEDL located at human chromosome Xp22 (12)(13)(14). SEDL (also known as Sedlin) is a component of human TRAPP as shown by an immunoblotting analysis (15).…”

Noncanonical and canonical splice sites: a novel mutation at the rare noncanonical splice-donor cut site (IVS4+1A>G) of SEDL causes variable splicing isoforms in X-linked spondyloepiphyseal dysplasia tarda

“…8 DNA extraction was performed using the salting-out method. 9 Exons 3, 4, 5 and 6 (containing the coding sequence) of SEDL and adjacent splice sites were amplified by PCR and sequenced in both directions, as described by Gedeon et al 1 Sequencing reactions were performed with Big-Dye terminators and an ABI 3730 automated sequencer. All of the sequences were compared against the normal sequences of unrelated controls and the UCSC and NCBI databases.…”

“…SEDL is a highly conserved gene with orthologs identified in yeast, flies and vertebrates, and it is widely expressed in tissues, including fibroblasts, lymphoblasts and fetal cartilage. 1 It contains six exons 2 and spans a genomic region of approximately 23 kb on Xp22 in the human genome; it also escapes from X-inactivation. 3 As a small gene with alternative splicing involving exon 2, 4 ubiquitously expressed SEDL mRNA is about 2.8 kb in size.…”