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Gene Review

SHOX  -  short stature homeobox

Homo sapiens

Synonyms: GCFX, PHOG, Pseudoautosomal homeobox-containing osteogenic protein, SHOXY, SS, ...
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Disease relevance of SHOX


Psychiatry related information on SHOX

  • The SS boys' self-perceptions of domain-specific competencies and global self-worth were comparable to a normative comparison group with the exception that older subjects (13 years or older) described their athletic abilities more positively and their work competence more negatively [6].
  • The SS boys were described by parents as being significantly less socially competent and showing more behavioral and emotional problems than a normative sample selected for mental health [6].
  • BDHI mean total scores and suspiciousness and negativism subscales scores were significantly higher in SS individuals, in comparison with LL subjects, among heroin addicts [7].

High impact information on SHOX


Chemical compound and disease context of SHOX


Biological context of SHOX

  • We identified submicroscopic PAR1 deletions encompassing the recently described short stature homeobox-containing gene SHOX (refs 7,8) segregating with the LWD phenotype in 5 families [9].
  • The results provide further support for the idea that clinical features in X chromosome aberrations are primarily explained by haploinsufficiency of SHOX and the lymphogenic gene and by the extent of chromosome imbalance in mitotic cells and pairing failure in meiotic cells [12].
  • The deletion size of each patient was determined by fluorescence in situ hybridization and microsatellite analyses for 38 Xp loci including SHOX, which was deleted in groups 1-3 and preserved in group 4 [12].
  • However, the only known disease gene within the pseudoautosomal regions is the SHORT STATURE HOMEBOX (SHOX) gene, functional loss of which is causally related to various short stature conditions and disturbed bone development [13].
  • Deletion of the SHOX region on the human sex chromosomes has been shown to result in idiopathic short stature and proposed to play a role in the short stature associated with Turner syndrome [14].

Anatomical context of SHOX

  • Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases [15].
  • Recent analyses have furthermore revealed that the phosphorylation-sensitive function of SHOX is directly involved in chondrocyte differentiation and maturation [13].
  • To enhance our understanding of the underlying mechanism of action, we have established a cell culture model consisting of four stably transfected cell lines and analysed the functional properties of the SHOX protein on a molecular level [16].
  • Results show that the SHOX-encoded protein is located exclusively within the nucleus of a variety of cell lines, including U2Os, HEK293, COS7 and NIH 3T3 cells [16].
  • The SHOX expression pattern in the limb and first and second pharyngeal arches not only explains SHOX -related short stature phenotypes, but also for the first time provides evidence for the involvement of this gene in the development of additional Turner stigmata [17].

Associations of SHOX with chemical compounds

  • Growth hormone and gonadotropin-releasing hormone analog therapy in haploinsufficiency of SHOX [18].
  • Furthermore, the similarity in the growth pattern between this female and patients with estrogen resistance or aromatase deficiency implies that the association of an extra copy of SHOX with gonadal estrogen deficiency may represent the further clinical entity for tall stature resulting from continued growth in late teens or into adulthood [11].
  • Here, we report that SHOX is phosphorylated exclusively on serine residues in vivo [19].
  • This C to T transition is predicted to cause an arginine to cysteine amino acid change in a highly conserved region of the recognition helix of the homeodomain, which may reduce the stability of the interaction between the SHOX protein and its target DNA [20].
  • Sterol and very long chain fatty acid profiles, FISH analysis for SHOX gene deletions, blood lymphocyte karyotype, and phytanic acid levels were normal in those tested, and no mutations in arylsulfatase D and E genes were detected [21].

Other interactions of SHOX

  • In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations [15].
  • The final karyotype was 46,Y,der(X)t(X; Y)(p22.3; q11.2).ish der(X) (DXZ1+, KAL+, STS-, SHOX-) mat [22].
  • Deficiencies or mutations in the human pseudoautosomal SHOX gene are associated with a series of short-stature conditions, including Turner syndrome, Leri-Weill dyschondrosteosis, and Langer mesomelic dysplasia [23].
  • Fluorescence in situ hybridization and microsatellite analyses for 19 loci/regions on the X chromosome demonstrated that the del(Xp) chromosome was missing SHOX and had the breakpoint between DMD and CYBB [24].
  • Further studies are necessary to investigate genotype/phenotype correlation in cases with translocations or microdeletions on Xp22.3, including the ARSE and the SHOX gene loci [25].

Analytical, diagnostic and therapeutic context of SHOX


  1. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). Belin, V., Cusin, V., Viot, G., Girlich, D., Toutain, A., Moncla, A., Vekemans, M., Le Merrer, M., Munnich, A., Cormier-Daire, V. Nat. Genet. (1998) [Pubmed]
  2. Complete SHOX deficiency causes Langer mesomelic dysplasia. Zinn, A.R., Wei, F., Zhang, L., Elder, F.F., Scott, C.I., Marttila, P., Ross, J.L. Am. J. Med. Genet. (2002) [Pubmed]
  3. Léri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3. Spranger, S., Schiller, S., Jauch, A., Wolff, K., Rauterberg-Ruland, I., Hager, D., Tariverdian, G., Tröger, J., Rappold, G. Am. J. Med. Genet. (1999) [Pubmed]
  4. SHOX intragenic microsatellite analysis in patients with short stature. Ezquieta, B., Cueva, E., Oliver, A., Gracia, R. Journal of pediatric endocrinology & metabolism : JPEM. (2002) [Pubmed]
  5. Translocation (Y;22) resulting in the loss of SHOX and isolated short stature. Borie, C., Léger, J., Dupuy, O., Hassan, M., Ledu, N., Lebbar, A., Czernichow, P., Eydoux, P. Am. J. Med. Genet. A (2004) [Pubmed]
  6. Short stature: a psychosocial burden requiring growth hormone therapy? Sandberg, D.E., Brook, A.E., Campos, S.P. Pediatrics (1994) [Pubmed]
  7. Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates. Gerra, G., Garofano, L., Santoro, G., Bosari, S., Pellegrini, C., Zaimovic, A., Moi, G., Bussandri, M., Moi, A., Brambilla, F., Donnini, C. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  8. Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX. May, C.A., Shone, A.C., Kalaydjieva, L., Sajantila, A., Jeffreys, A.J. Nat. Genet. (2002) [Pubmed]
  9. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis. Shears, D.J., Vassal, H.J., Goodman, F.R., Palmer, R.W., Reardon, W., Superti-Furga, A., Scambler, P.J., Winter, R.M. Nat. Genet. (1998) [Pubmed]
  10. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Rao, E., Weiss, B., Fukami, M., Rump, A., Niesler, B., Mertz, A., Muroya, K., Binder, G., Kirsch, S., Winkelmann, M., Nordsiek, G., Heinrich, U., Breuning, M.H., Ranke, M.B., Rosenthal, A., Ogata, T., Rappold, G.A. Nat. Genet. (1997) [Pubmed]
  11. Short stature homeobox-containing gene duplication on the der(X) chromosome in a female with 45,X/46,X, der(X), gonadal dysgenesis, and tall stature. Ogata, T., Kosho, T., Wakui, K., Fukushima, Y., Yoshimoto, M., Miharu, N. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  12. Turner syndrome and Xp deletions: clinical and molecular studies in 47 patients. Ogata, T., Muroya, K., Matsuo, N., Shinohara, O., Yorifuji, T., Nishi, Y., Hasegawa, Y., Horikawa, R., Tachibana, K. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  13. The pseudoautosomal regions, SHOX and disease. Blaschke, R.J., Rappold, G. Curr. Opin. Genet. Dev. (2006) [Pubmed]
  14. SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development. Blaschke, R.J., Monaghan, A.P., Schiller, S., Schechinger, B., Rao, E., Padilla-Nash, H., Ried, T., Rappold, G.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia. Grigelioniene, G., Eklöf, O., Ivarsson, S.A., Westphal, O., Neumeyer, L., Kedra, D., Dumanski, J., Hagenäs, L. Hum. Genet. (2000) [Pubmed]
  16. The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator. Rao, E., Blaschke, R.J., Marchini, A., Niesler, B., Burnett, M., Rappold, G.A. Hum. Mol. Genet. (2001) [Pubmed]
  17. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome. Clement-Jones, M., Schiller, S., Rao, E., Blaschke, R.J., Zuniga, A., Zeller, R., Robson, S.C., Binder, G., Glass, I., Strachan, T., Lindsay, S., Rappold, G.A. Hum. Mol. Genet. (2000) [Pubmed]
  18. Growth hormone and gonadotropin-releasing hormone analog therapy in haploinsufficiency of SHOX. Ogata, T., Onigata, K., Hotsubo, T., Matsuo, N., Rappold, G. Endocr. J. (2001) [Pubmed]
  19. Phosphorylation on Ser106 modulates the cellular functions of the SHOX homeodomain protein. Marchini, A., Daeffler, L., Marttila, T., Schneider, K.U., Blaschke, R.J., Schnölzer, M., Rommelaere, J., Rappold, G. J. Mol. Biol. (2006) [Pubmed]
  20. Pseudodominant inheritance of Langer mesomelic dysplasia caused by a SHOX homeobox missense mutation. Shears, D.J., Guillen-Navarro, E., Sempere-Miralles, M., Domingo-Jimenez, R., Scambler, P.J., Winter, R.M. Am. J. Med. Genet. (2002) [Pubmed]
  21. Longterm follow-up in chondrodysplasia punctata, tibia-metacarpal type, demonstrating natural history. Savarirayan, R., Boyle, R.J., Masel, J., Rogers, J.G., Sheffield, L.J. Am. J. Med. Genet. A (2004) [Pubmed]
  22. An Xp; Yq translocation causing a novel contiguous gene syndrome in brothers with generalized epilepsy, ichthyosis, and attention deficits. Doherty, M.J., Glass, I.A., Bennett, C.L., Cotter, P.D., Watson, N.F., Mitchell, A.L., Bird, T.D., Farrell, D.F. Epilepsia (2003) [Pubmed]
  23. A mouse model for human short-stature syndromes identifies Shox2 as an upstream regulator of Runx2 during long-bone development. Cobb, J., Dierich, A., Huss-Garcia, Y., Duboule, D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  24. Del(X)(p21.1) in a mother and two daughters: genotype-phenotype correlation of Turner features. Adachi, M., Tachibana, K., Asakura, Y., Muroya, K., Ogata, T. Hum. Genet. (2000) [Pubmed]
  25. Brachytelephalangic dwarfism due to the loss of ARSE and SHOX genes resulting from an X;Y translocation. Seidel, J., Schiller, S., Kelbova, C., Beensen, V., Orth, U., Vogt, S., Claussen, U., Zintl, F., Rappold, G.A. Clin. Genet. (2001) [Pubmed]
  26. Expression of SHOX in human fetal and childhood growth plate. Munns, C.J., Haase, H.R., Crowther, L.M., Hayes, M.T., Blaschke, R., Rappold, G., Glass, I.A., Batch, J.A. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  27. SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability. Jorge, A.A., Souza, S.C., Nishi, M.Y., Billerbeck, A.E., Lib??rio, D.C., Kim, C.A., Arnhold, I.J., Mendonca, B.B. Clin. Endocrinol. (Oxf) (2007) [Pubmed]
  28. A man who inherited his SRY gene and Leri-Weill dyschondrosteosis from his mother and neurofibromatosis type 1 from his father. Wei, F., Cheng, S., Badie, N., Elder, F., Scott, C., Nicholson, L., Ross, J.L., Zinn, A.R. Am. J. Med. Genet. (2001) [Pubmed]
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