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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Vogel, F. & Motulsky, M.D. Human Genetics. Problems and Approaches (Springer-Verlag, Berlin, Heidelberg, New York, 1997).
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).
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).
Leung, D.W. et al. Molecular basis for familial isolated growth hormone deficiency. Proc. Natl. Acad. Sd. USA 330, 537–543 (1987).
Goddard, A.D. et al. 333, 1093–1098 (1995).
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).
Rousseau, F. et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252–254 (1994).
Muenke, M. & Schell, U. Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet. 11, 308–313 (1995).
Hecht, J.T. et al. Mutation in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondrodysplasia. Nature Genet. 10, 325–329 (1995).
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).
Kotzot, D. et al. Uniparental disomy 7 in Silver-Russel syndrome and primordial growth retardation. Hum. Mol. Genet. 4, 583–587 (1995).
Ranke, M.B. Towards a consensus on the definition of idiopathic short stature. Horm. Res. 45, 64–67 (1996).
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).
Ullrich, O. Über typische Kombinationsbilder multipler Abartung. Kinderheilkunde 49, 271–276 1930).
Turner, H.H. A syndrome of infantilism, congenital webbed neck, and cubrtus valgus. Endocrinology 23, 566–674 (1938).
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).
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).
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).
Schaefer, L. et al. A high resolution deletion map of human chromosome Xp22. Nature Genet. 4, 272–279 (1993).
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).
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).
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).
Ried, K. et al. Characterization of a yeast artificial chromosome contig spanning the pseudoautosomal region. Genomics 29, 787–792 (1995).
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).
Solovyev, V.V. & Salamov, A.A., Salamov, A. http://genome.imb-jena.de/genomedocs/ notes23.html
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).
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).
Kessel, M. & Gruss, P. Homeotic transformations of murine vertebrae and concomitant alteration of Hoxcodes induced by retinoicacid. Cell 67, 89–104 (1991).
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).
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).
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).
Rovescalli, A.C., Asoh, S. & Nirenberg, M. Cloning and characterization of four murine homeobox genes. Proc. Natl. Acad. Sci. USA 93, 10691–10696 (1996).
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).
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).
Anderson, B. & Rosenfeld, M.G. Pit-1 determines cell types during development of the anterior pituitary gland. J. Biol. Chem. 269, 29335–29338 (1994).
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).
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).
Petrij, F. et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348–351 (1995).
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).
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).
Rosenfeld, R.G. et al. Recommendation for diagnosis, treatment, and management of individuals with Turner syndrome. Endocrinotogist 4, 351–358 (1996).
Hall, J.G. & Gllchrist, D.M. Turner syndrome and its variants. Pediatr. Clin. N. Am. 37, 1421–1436 (1990).
Robinson, A. Demography and Prevalence of Turner Syndrome. (Marcel Dekker, New York, 1990).
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).
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).
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).
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).
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).
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).
Burgoyne, S.P. Thumbs down for zinc finger? Nature 342, 860–862 (1989).
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).
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).
Disteche, C.M. et al. The human pseudoautosomal GM-CSFreceptor subunit gene is autosomal in mouse. Nature Genet. 1, 333–336 (1992).
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).
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).
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).
Bairoch, A. PROSITE: a dictionary of sites and patterns in proteins. Nucl. Adds Res. 20, suppl 2013–2018 (1992).
Gout, I. et al. The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell 75, 25–36 (1993).
Ren, R., Mayer, B.J., Cicchetti, P. & Baltimore, D. Identification of a ten-amino acid proline-richSHS binding site. Science 259, 1157–1161 (1993).
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).
Ogata, T. & Matsuo, N., Matsuo, N. (1997). The Y-specific growth gene(s): how does it promote the stature? (in the press).
Lichter, P. & Cremer, T., Cytogenetics: A Practical Approach (IRUOxford Univ. Press, Oxford/New York/Tokyo, 1992).
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).
Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).
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).
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).
QiagenTGGE Handbook, DiagenGmbH, TGMA41123/93. (1993).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0597-54
This article is cited by
-
Review of published 467 achondroplasia patients: clinical and mutational spectrum
Orphanet Journal of Rare Diseases (2024)
-
X chromosome dosage and the genetic impact across human tissues
Genome Medicine (2023)
-
Competing endogenous RNA network analysis of Turner syndrome patient-specific iPSC-derived cardiomyocytes reveals dysregulation of autosomal heart development genes by altered dosages of X-inactivation escaping non-coding RNAs
Stem Cell Research & Therapy (2023)
-
PGCLCs of human 45,XO reveal pathogenetic pathways of neurocognitive and psychosocial disorders
Cell & Bioscience (2022)
-
Targeting G-quadruplex for rescuing impaired chondrogenesis in WRN-deficient stem cells
Cell & Bioscience (2022)