title: A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda.
abstract: Spondyloepiphyseal dysplasia tarda (SEDL) is a genetically heterogeneous disorder characterized by mild-to-moderate short stature and early-onset osteoarthritis. Both autosomal and X-linked forms have been described. Elsewhere, we have reported the identification of the gene for the X-linked recessive form, which maps to Xp22.2. We now report characterization of an exon-skipping mutation (IVS3+5G-->A at the intron 3 splice-donor site) in two unrelated families with SEDL. Using reverse transcriptase (RT)-PCR, we demonstrated that the mutation resulted in elimination of the first 31 codons of the open reading frame. The mutation was not detected in 120 control X chromosomes. Articular cartilage from an adult who had SEDL and carried this mutation contained chondrocytes with abundant Golgi complexes and dilated rough endoplasmic reticulum (ER). RT-PCR experiments using mouse/human cell hybrids revealed that the SEDL gene escapes X inactivation. Homologues of the SEDL gene include a transcribed retropseudogene on chromosome 19, as well as expressed genes in mouse, rat, Drosophila melanogaster Caenorhabditis elegans, and Saccharomyces cerevisiae. The latter homologue, p20, has a putative role in vesicular transport from ER to Golgi complex. These data suggest that SEDL mutations may perturb an intracellular pathway that is important for cartilage homeostasis.
authors.affiliation: Department of Pediatrics and Program in Human Genetics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. george.tiller@mcmail.vanderbilt.edu
authors.forename: G E
authors.initials: GE
authors.lastname: Tiller
authors.forename: V L
authors.initials: VL
authors.lastname: Hannig
authors.forename: D
authors.initials: D
authors.lastname: Dozier
authors.forename: L
authors.initials: L
authors.lastname: Carrel
authors.forename: K C
authors.initials: KC
authors.lastname: Trevarthen
authors.forename: W R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: S
authors.initials: S
authors.lastname: Mundlos
authors.forename: J L
authors.initials: JL
authors.lastname: Haines
authors.forename: A K
authors.initials: AK
authors.lastname: Gedeon
authors.forename: J
authors.initials: J
authors.lastname: Gecz
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016384:Consensus Sequence / Q000235:genetics; D004252:DNA Mutational Analysis; D004303:Dosage Compensation, Genetic; D018870:Endoplasmic Reticulum, Rough / Q000473:pathology / Q000648:ultrastructure; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D006056:Golgi Apparatus / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D006822:Hybrid Cells; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000151:congenital / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D021381:Protein Transport; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014157:Transcription Factors; D014960:X Chromosome / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; C120759:TRAPPC2 protein, human; D014157:Transcription Factors