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Type: Journal article
Title: A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda
Author: Tiller, G.
Hannig, V.
Dozier, D.
Carrel, L.
Trevarthen, K.
Wilcox, W.
Mundlos, S.
Haines, J.
Gedeon, A.
Gecz, J.
Citation: American Journal of Human Genetics, 2001; 68(6):1398-1407
Publisher: Univ Chicago Press
Issue Date: 2001
ISSN: 0002-9297
Statement of
Tiller, George E. ; Hannig, Vickie L. ; Dozier, Damon ; Carrel, Laura ; Trevarthen, Karrie C. ; Wilcox, William R. ; Mundlos, Stefan ; Haines, Jonathan L. ; Gedeon, Agi K. ; Gecz, Jozef
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.
Keywords: Cartilage; Cells, Cultured; Hybrid Cells; X Chromosome; Endoplasmic Reticulum, Rough; Golgi Apparatus; Chondrocytes; Animals; Humans; Osteochondrodysplasias; Carrier Proteins; Membrane Transport Proteins; Transcription Factors; RNA, Messenger; RNA Splice Sites; Pedigree; DNA Mutational Analysis; RNA Splicing; Base Sequence; Consensus Sequence; Protein Transport; Phenotype; Mutation; Exons; Molecular Sequence Data; Adult; Middle Aged; Dosage Compensation, Genetic; Female; Male; Genetic Linkage
RMID: 0020010880
DOI: 10.1086/320594
Appears in Collections:Paediatrics publications

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