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Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome

Abstract

Growth retardation resulting in short stature is a major concern for parents and due to its great variety of causes, a complex diagnostic challenge for clinicians. A major locus involved in linear growth has been implicated within the pseudoautosomal region (PAR1) of the human sex chromosomes. We have determined an interval of 170 kb of DNA within PAR1 which was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. We have isolated a homeobox-containing gene (SHOX} from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression. We also identified one functionally significant SHOX mutation by screening 91 individuals with idiopathic short stature. Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients.

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References

  1. Vogel, F. & Motulsky, M.D. Human Genetics. Problems and Approaches (Springer-Verlag, Berlin, Heidelberg, New York, 1997).

    Book  Google Scholar 

  2. Martial, J.A., Hallewell, R.A., Baxter, J.D. & Goodman, H.M. Human growth hormone: complementary DNA cloning and expression in bacteria. Science 205, 602–607 (1979).

    Article  CAS  Google Scholar 

  3. Phillips, J.A. III, Hjelle, B.L., Seeburg, P.M. & Zachmann, M. Molecular basis for familial isolated growth hormone deficiency. Proc. Natl. Acad. Sd. USA 78, 6372–6375 (1981).

    Article  CAS  Google Scholar 

  4. Leung, D.W. et al. Molecular basis for familial isolated growth hormone deficiency. Proc. Natl. Acad. Sd. USA 330, 537–543 (1987).

    CAS  Google Scholar 

  5. Goddard, A.D. et al. 333, 1093–1098 (1995).

  6. Shiang, R. et al. Mutation in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondrodysplasia. Cell 78, 335–342 (1994).

    Article  CAS  Google Scholar 

  7. Rousseau, F. et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252–254 (1994).

    Article  CAS  Google Scholar 

  8. Muenke, M. & Schell, U. Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet. 11, 308–313 (1995).

    Article  CAS  Google Scholar 

  9. Hecht, J.T. et al. Mutation in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondrodysplasia. Nature Genet. 10, 325–329 (1995).

    Article  CAS  Google Scholar 

  10. Briggs, M.D. et al. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nature Genet. 10, 330–336 (1995).

    Article  CAS  Google Scholar 

  11. Kotzot, D. et al. Uniparental disomy 7 in Silver-Russel syndrome and primordial growth retardation. Hum. Mol. Genet. 4, 583–587 (1995).

    Article  CAS  Google Scholar 

  12. Ranke, M.B. Towards a consensus on the definition of idiopathic short stature. Horm. Res. 45, 64–67 (1996).

    Article  CAS  Google Scholar 

  13. Ogata, T. & Matsuo, N. Sex chromosome aberrations and short stature: deduction of the principal factors involved in the determination of adult height. Hum. Genet. 91, 551–562 (1993).

    Article  CAS  Google Scholar 

  14. Ullrich, O. Über typische Kombinationsbilder multipler Abartung. Kinderheilkunde 49, 271–276 1930).

    Article  Google Scholar 

  15. Turner, H.H. A syndrome of infantilism, congenital webbed neck, and cubrtus valgus. Endocrinology 23, 566–674 (1938).

    Article  Google Scholar 

  16. Zuffardi, O. et al. The role of Yp in sex determination: new evidence from X/Y translocations. Am. J. Med. Genet. 12, 175–184 (1982).

    Article  CAS  Google Scholar 

  17. Curry, C.J.R. et al. Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X-chromosome. N. Engl.J. Med. 311, 1010–1015 (1984).

    Article  CAS  Google Scholar 

  18. Ballabio, A. et al. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc. Natl. Acad. Sd. USA 86, 10001–10005 (1989).

    Article  CAS  Google Scholar 

  19. Schaefer, L. et al. A high resolution deletion map of human chromosome Xp22. Nature Genet. 4, 272–279 (1993).

    Article  CAS  Google Scholar 

  20. Ogata, T., Goodfellow, P., Petit, C., Aya, M. & Matsuo, N. Short stature in a girl with a terminal Xp deletion distal to DXYS15: localisation of a growth gene(s) in the pseudoautosomal region. J. Med. Genet. 29, 455–459 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ogata, T. et al. Short stature in a girl with partial monosomy of the pseudoautosomal region distal to DXYS15: further evidence for the assignement of the critical region for a pseudoautosomal growth gene(s). J. Med. Genet. 32, 831–834 (1995).

    Article  CAS  Google Scholar 

  22. Henke, A. et al. Deletions within the pseudoautosomal region help map three new markers and indicate a possible role of this region in linear growth. Am. J. Hum. Genet. 49, 811–819 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ried, K. et al. Characterization of a yeast artificial chromosome contig spanning the pseudoautosomal region. Genomics 29, 787–792 (1995).

    Article  CAS  Google Scholar 

  24. Yaspo, M.L. et al. Model for a transcript map of human chromosome 21: isolation of new coding sequences from exon and enriched cDNA libraries. Hum. Mol. Genet. 4, 1291–1304 (1995).

    Article  CAS  Google Scholar 

  25. Solovyev, V.V. & Salamov, A.A., Salamov, A. http://genome.imb-jena.de/genomedocs/ notes23.html

  26. Uberbacher, E.C. & Mural, R.J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl. Acad. Sci. USA 88, 11261–11265(1991).

    Article  CAS  Google Scholar 

  27. Thomas, A. & Skolnick, M.H. A probabilistic model for detecting coding regions in DNA sequences. IMA J. Math.Appl. Med. Biol. 11, 149–160 (1994).

    Article  CAS  Google Scholar 

  28. Kessel, M. & Gruss, P. Homeotic transformations of murine vertebrae and concomitant alteration of Hoxcodes induced by retinoicacid. Cell 67, 89–104 (1991).

    Article  CAS  Google Scholar 

  29. Ferrari, D., Kosher, R.A. & Dealy, C.N. Limb mesenchymal cells inhibited from undergoing cartilage differentiation by a tumor promoting phorbol ester maintain expression of the homeobox-containing gene MSX1 and fail to exhibit gap junctional communication. Biochem. Biophys. Res. Comm. 205, 429–434 (1994).

    Article  CAS  Google Scholar 

  30. Cheng, T., Wang, Y. & Dai, W. Trancription factor egr-1 is involved in phorbol 12-myristate 13-acetate-induced megakaryocytic differentiation of K562 cells. J. Biol. Chem. 269, 30848–30853 (1994).

    CAS  PubMed  Google Scholar 

  31. Manohar, C.F., Salwen, H.R., Furtado, M.R. & Cohn, S.L. Up-regulation of HOXC6, HOXD1 and HOXD8homeobox gene expression in human neuroblastoma cells following chemical induction of differentiation. Tumor Biol. 17, 34–47 (1996).

    Article  CAS  Google Scholar 

  32. Rovescalli, A.C., Asoh, S. & Nirenberg, M. Cloning and characterization of four murine homeobox genes. Proc. Natl. Acad. Sci. USA 93, 10691–10696 (1996).

    Article  CAS  Google Scholar 

  33. Schiebel, K., Weiss, B., Wφhrle, D. & Rappold, G.A. A human pseudoautosomal gene, ADP/ATP translocase, excapes X-inactivation whereas a homologue on Xq is subject to X-inactivation. Nature Genet. 3, 82–87 (1993).

    Article  CAS  Google Scholar 

  34. Li, S. et al. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene P/M. Nature 347, 528–533 (1990).

    Article  CAS  Google Scholar 

  35. Anderson, B. & Rosenfeld, M.G. Pit-1 determines cell types during development of the anterior pituitary gland. J. Biol. Chem. 269, 29335–29338 (1994).

    Google Scholar 

  36. Baldwin, C.T., Hoth, C.F., Amos, J.A., da-Silva, E.O. & Milunsky, A. An exonk mutation in the HuP2paired domain gene causes Waardenburg's syndrome. Nature 355, 637–638 (1992).

    Article  CAS  Google Scholar 

  37. Tassabehji, M. et al. Waardenburg sydrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature 355, 635–636 (1992).

    Article  CAS  Google Scholar 

  38. Petrij, F. et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348–351 (1995).

    Article  CAS  Google Scholar 

  39. Ton, C.C.T. et al. Positional cloning and characterization of a paired box- and homeobox-containing gene from the Aniridia region. Cell 67, 1059–1074 (1991).

    Article  CAS  Google Scholar 

  40. Bardoni, B. et al. A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genet. 7, 497–501 (1994).

    Article  CAS  Google Scholar 

  41. Rosenfeld, R.G. et al. Recommendation for diagnosis, treatment, and management of individuals with Turner syndrome. Endocrinotogist 4, 351–358 (1996).

    Article  Google Scholar 

  42. Hall, J.G. & Gllchrist, D.M. Turner syndrome and its variants. Pediatr. Clin. N. Am. 37, 1421–1436 (1990).

    Article  CAS  Google Scholar 

  43. Robinson, A. Demography and Prevalence of Turner Syndrome. (Marcel Dekker, New York, 1990).

  44. Magenis, R.E. et al. Turner syndrome resulting from partial deletion of Y-chromosome short arm: localization of male determinants. J. Pediat. 105, 916–919 (1984).

    Article  CAS  Google Scholar 

  45. Disteche, C.M. et al. Small deletions of the short arm of the Y-chromosome in 46.XY females. Proc. Natl. Acad. Sci. USA 83, 7841–7844 (1986).

    Article  CAS  Google Scholar 

  46. Levilliers, J., Quack, B., Weissenbach, J. & Petit, C. Exchange of terminal portions of X-and Y-chromosomal short arms in human XY females. Proc. Natl. Acad. Sd. USA 86, 2296–2300 (1989).

    Article  CAS  Google Scholar 

  47. Ogata, T., Tyler-Smith, C., Purvis-Smith, S. & Turner, G. Chromosomal localisation of a gene(s) for Turner stigmata on Yp. J. Med. Genet. 30, 918–922 (1993).

    Article  CAS  Google Scholar 

  48. Barbaux, S. et al. Proximal deletions of the long arm of the Y chromosome suggest a critical region associated with a specific subset of characteristic Turner stigmata. Hum. Mol. Genet. 4, 1565–1568 (1995).

    Article  CAS  Google Scholar 

  49. Fisher, E.M.C. et al. Homologous ribosomal protein genes on the human X and Y chromosomes: Escape from X inactivation and possible implication for Turner syndrome. Cell 63, 1205–1218 (1990).

    Article  CAS  Google Scholar 

  50. Burgoyne, S.P. Thumbs down for zinc finger? Nature 342, 860–862 (1989).

    Article  CAS  Google Scholar 

  51. Ashworth, A., Rastan, S., Lovell-Badge, R. & Kay, G. X-chromosome inactivation may explain the difference in viability of XO humans and mice. Nature 351, 406–408 (1991).

    Article  CAS  Google Scholar 

  52. Burgoyne, P.S., Evans, E.P. & Holland, K. XO monosomy is associated with reduced birthweight and lowered weight gain in the mouse. J. Keprod. Fertil. 68, 381–385 (1983).

    Article  CAS  Google Scholar 

  53. Disteche, C.M. et al. The human pseudoautosomal GM-CSFreceptor subunit gene is autosomal in mouse. Nature Genet. 1, 333–336 (1992).

    Article  CAS  Google Scholar 

  54. Milatovich, A., Kitamura, T., Miyajima, A. & Francke, U. Gene for the alpha-subunit of the human interleukin-3 receptor (IL3KA) localized to the X-Y pseudoautosomal region. Am. J. Hum. Genet. 53, 1146–1153 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lehrach, H. et al. Hybridisation fingerprinting in genome mapping and sequencing, in Genome Analysis Vol. 1 (eds Davies K.E., Tllghman, S.) (Cold Spring Harbor-Laboratory Press, Cold Spring Harbor, New York, 1990).

    Google Scholar 

  56. Page, D.C. et al. Linkage, physical mapping and DNA sequence analysis of pseudoautosomal loci on the human X and Y chromosomes. Genomics 1, 243–256 (1987).

    Article  CAS  Google Scholar 

  57. Bairoch, A. PROSITE: a dictionary of sites and patterns in proteins. Nucl. Adds Res. 20, suppl 2013–2018 (1992).

    Article  CAS  Google Scholar 

  58. Gout, I. et al. The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell 75, 25–36 (1993).

    Article  CAS  Google Scholar 

  59. Ren, R., Mayer, B.J., Cicchetti, P. & Baltimore, D. Identification of a ten-amino acid proline-richSHS binding site. Science 259, 1157–1161 (1993).

    Article  CAS  Google Scholar 

  60. Kulharya, A.S. et al. Mild phenotypic effects of a de novo deletion Xpter → Xp22.3 and duplication 3pter → 3p23. Am. J. Med. Genet 56, 16–21 (1995).

    Article  CAS  Google Scholar 

  61. Ogata, T. & Matsuo, N., Matsuo, N. (1997). The Y-specific growth gene(s): how does it promote the stature? (in the press).

  62. Lichter, P. & Cremer, T., Cytogenetics: A Practical Approach (IRUOxford Univ. Press, Oxford/New York/Tokyo, 1992).

    Google Scholar 

  63. Burn, T.C., Connors, T.D., Klinger, K.W. & Landes, M.L. Increased exon-trapping efficiency through modification to the pSPL3 splicing vector. Gene 161, 183–187 (1995).

    Article  CAS  Google Scholar 

  64. Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).

    Article  CAS  Google Scholar 

  65. Frohman, M.A., Dush, M.K. & Martin, G.R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc. Natl. Acad. Sci. USA 85, 8998–9020 (1988).

    Article  CAS  Google Scholar 

  66. Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).

    Article  CAS  Google Scholar 

  67. QiagenTGGE Handbook, DiagenGmbH, TGMA41123/93. (1993).

Download references

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Correspondence to Gudrun A. Rappold.

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Rao, E., Weiss, B., Fukami, M. et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16, 54–63 (1997). https://doi.org/10.1038/ng0597-54

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