Abstract
Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people1. 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 complications2,3,4. 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 arthroplasty3,4,5. Obligate female carriers are generally clinically and radiographically indistinguishable from the general population4,5, although some cases have phenotypic changes consistent with expression of the gene defect2,4,6,7. 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.
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References
Wynne-Davies, R. & Gormley, J. The prevalence of skeletal dysplasias. An estimate of their minimum frequency and the number of patients requiring orthopaedic care. J. Bone Joint Surg. [Br] 67, 133–137 (1985).
Bannerman, R.M., Ingall, G.B. & Mohn, J.F. X-linked spondyloepiphyseal dysplasia tarda: clinical and linkage data. J. Med. Genet. 8, 291–301 (1971).
Iceton, J.A. & Horne, G. Spondylo-epiphyseal dysplasia tarda: the X-linked variety in three brothers. J. Bone Joint Surg. [Br] 68, 616–619 (1986).
MacKenzie, J.J. et al. X linked spondyloepiphyseal dysplasia: a clinical, radiological, and molecular study of a large kindred. J. Med. Genet. 33, 823–828 (1996).
Harper, P.S., Jenkins, P. & Laurence, K.M. Spondylo-epiphyseal dysplasia tarda: a report of four cases in two families. Br. J. Radiol. 46, 676–684 (1973).
Gottesman, G.S., McAlister, W.H., Eddy, M.C., Mueller, J.G. & Whyte, M.P. X-linked spondyloepiphyseal dysplasia tarda: report of a six-generation kindred, carrier detection and natural progression. J. Bone Min. Res. 11 (suppl. 1), S252–257 (1996).
Whyte, M.P., Gottesman, G.S., Eddy, M.C. & McAlister, W.H. X-linked recessive spondyloepiphyseal dysplasia tarda: clinical and radiographic evolution in a 6-generation kindred and review of the literature. Medicine 78, 9–25 (1999).
Szpiro-Tapia, S. et al. Spondyloepiphyseal dysplasia tarda: linkage with genetic markers from the distal short arm of the X chromosome. Hum. Genet. 81, 61–63 (1988).
Heuertz, S. et al. The gene for spondyloepiphyseal dysplasia (SEDL) maps to Xp22 between DXS16 and DXS92. Genomics 18, 100–104 (1993).
Heuertz, S. et al. Genetic mapping of Xp22.12–p22.31, with a refined localization for spondyloepiphyseal dysplasia (SEDL). Hum. Genet. 96, 407–410 (1995).
Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).
Ferrero, G.B. et al. An integrated physical and genetic map of a 35 Mb region on chromosome Xp22.3–Xp21.3. Hum. Mol. Genet. 4, 1821–1827 (1995).
de Conciliis, L. et al. Characterisation of Cxorf5 (71-7A), a novel human cDNA mapping to Xp22 and encoding a protein containing coiled-coil α-helical domains. Genomics 51, 243–250 (1998).
Davies, J.P., Cotter, P.D. & Ioannou, Y.A. Cloning and mapping of human Rab7 and Rab9 cDNA sequences and identification of a Rab9 pseudogene. Genomics 41, 131–134 (1997).
Narayanan, V., Olinsky, S., Dahle, E., Naidu, S. & Zoghbi, H.Y. Mutation analysis of the M6B gene in patients with Rett syndrome. Am. J. Med. Genet. 78, 165–168 (1998).
Sacher, M. et al. TRAPP, a highly conserved novel complex on the cis-Golgi that mediates vesicle docking and fusion. EMBO J. 17, 2494–2503 (1998).
Rossi, G., Kolstad, K., Stone, S., Palluault, F. & Ferro-Novick, S. BET3 encodes a novel hydrophilic protein that acts in conjunction with yeast SNAREs. Mol. Biol. Cell 6, 1769–1780 (1995).
Hastbacka, J. et al. The diastrophic dysplasia gene encodes a novel sulphate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78, 1073–1087 (1994).
Ul Haque, F.M. et al. Mutations in orthologous genes in human spondyloepiphyseal dysplasia and the brachyomorphic mouse. Nature Genet. 20, 157–162 (1998).
Chang, Y.P.C., Smith, K.D. & Dover, G.J. Dinucleotide repeat polymorphisms at the DXS85, DXS16 and DXS43 loci. Hum. Mol. Genet. 3, 1029 (1994).
Lathrop, G.M. & Lalouel, J.M. Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460–465 (1984).
Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).
Chomczynski, P. & Sacci, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).
Acknowledgements
We thank family members for participation; G. Hallas, S. McDonnell and D. Dozier for technical assistance; and G. Turner for making available the clinical case notes for family 1. This work was supported by the National Health and Medical Research Council of Australia and a Shannon award (R55 AR45477) from the NIH.
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Gedeon, Á., Colley, A., Jamieson, R. et al. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nat Genet 22, 400–404 (1999). https://doi.org/10.1038/11976
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DOI: https://doi.org/10.1038/11976
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