Short-stature homeobox gene explained

The short-stature homeobox gene (SHOX), also known as short-stature-homeobox-containing gene, is a gene located on both the X and Y chromosomes, which is associated with short stature in humans if mutated or present in only one copy (haploinsufficiency).

Pathology

SHOX was first found during a search for the cause of short stature in women with Turner syndrome, where there is loss of genetic material from the X chromosome, typically by loss of one entire X chromosome.^[1]

Since its discovery, the gene has been found to play a role in idiopathic short stature, Léri-Weill dyschondrosteosis, and Langer mesomelic dysplasia.

Gene dosage effects of extra copies of SHOX may be a cause of the increased stature seen in other sex chromosome aneuploidy conditions such as triple X, XYY, Klinefelter, XXYY and similar syndromes.^[2]

Genetics and function

SHOX is composed of 6 different exons and is located in the pseudoautosomal region 1 (PAR1) of the X chromosome (Xp22.33) and Y chromosome.^[1] Since genes in PAR escape X inactivation, their dosage changes with sex chromosome aneuploidies such as Turner.^[3]

Similar genes are present in a variety of animals and insects.

It is a homeobox gene, meaning that it helps to regulate development.

Further reading

• Bernasconi S, Mariani S, Falcinelli C, Milioli S, Iughetti L, Forabosco A . SHOX gene in Leri-Weill syndrome and in idiopathic short stature . Journal of Endocrinological Investigation . 24 . 9 . 737–41 . October 2001 . 11716161 . 10.1007/bf03343919 . 44532326 . 11380/613021 .
• Leka SK, Kitsiou-Tzeli S, Kalpini-Mavrou A, Kanavakis E . Short stature and dysmorphology associated with defects in the SHOX gene . Hormones . 5 . 2 . 107–18 . 2006 . 16807223 . 10.14310/horm.2002.11174 . free .
• Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Campbell L, Hamel B, Ferguson-Smith MA, Gimelli G, Fraccaro M . 6 . Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome . Proceedings of the National Academy of Sciences of the United States of America . 86 . 24 . 10001–5 . December 1989 . 2602357 . 298630 . 10.1073/pnas.86.24.10001 . 1989PNAS...8610001B . free .
• Zuffardi O, Maraschio P, Lo Curto F, Müller U, Giarola A, Perotti L . The role of Yp in sex determination: new evidence from X/Y translocations . American Journal of Medical Genetics . 12 . 2 . 175–84 . June 1982 . 6954848 . 10.1002/ajmg.1320120207 .
• Kuznetzova T, Baranov A, Ivaschenko T, Savitsky GA, Lanceva OE, Wang MR, Giollant M, Malet P, Kascheeva T, Vakharlovsky V . 6 . X;Y translocation in a girl with short stature and some features of Turner's syndrome: cytogenetic and molecular studies . Journal of Medical Genetics . 31 . 8 . 649–51 . August 1994 . 7815426 . 1050031 . 10.1136/jmg.31.8.649 .
• Ogata T, Yoshizawa A, Muroya K, Matsuo N, Fukushima Y, Rappold G, Yokoya S . Short stature in a girl with partial monosomy of the pseudoautosomal region distal to DXYS15: further evidence for the assignment of the critical region for a pseudoautosomal growth gene(s) . Journal of Medical Genetics . 32 . 10 . 831–4 . October 1995 . 8558568 . 1051714 . 10.1136/jmg.32.10.831 .
• 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 MH, Ranke MB, Rosenthal A, Ogata T, Rappold GA . 6 . Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome . Nature Genetics . 16 . 1 . 54–63 . May 1997 . 9140395 . 10.1038/ng0597-54 . 26248561 .
• Rao E, Weiss B, Fukami M, Mertz A, Meder J, Ogata T, Heinrich U, Garcia-Heras J, Schiebel K, Rappold GA . 6 . FISH-deletion mapping defines a 270-kb short stature critical interval in the pseudoautosomal region PAR1 on human sex chromosomes . Human Genetics . 100 . 2 . 236–9 . August 1997 . 9254856 . 10.1007/s004390050497 . 33963012 .
• Ellison JW, Wardak Z, Young MF, Gehron Robey P, Laig-Webster M, Chiong W . PHOG, a candidate gene for involvement in the short stature of Turner syndrome . Human Molecular Genetics . 6 . 8 . 1341–7 . August 1997 . 9259282 . 10.1093/hmg/6.8.1341 . free .
• Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, Vekemans M, Le Merrer M, Munnich A, Cormier-Daire V . 6 . SHOX mutations in dyschondrosteosis (Leri-Weill syndrome) . Nature Genetics . 19 . 1 . 67–9 . May 1998 . 9590292 . 10.1038/ng0198-67 . 45129174 .
• Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Reardon W, Superti-Furga A, Scambler PJ, Winter RM . 6 . Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis . Nature Genetics . 19 . 1 . 70–3 . May 1998 . 9590293 . 10.1038/ng0198-70 . 25651344 .
• Grigelioniene G, Eklöf O, Ivarsson SA, Westphal O, Neumeyer L, Kedra D, Dumanski J, Hagenäs L . 6 . Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia . Human Genetics . 107 . 2 . 145–9 . August 2000 . 11030412 . 10.1007/s004390000352 . 27508795 .
• Huber C, Cusin V, Le Merrer M, Mathieu M, Sulmont V, Dagoneau N, Munnich A, Cormier-Daire V . 6 . SHOX point mutations in dyschondrosteosis . Journal of Medical Genetics . 38 . 5 . 323 . May 2001 . 11403039 . 1734877 . 10.1136/jmg.38.5.323 .
• Rao E, Blaschke RJ, Marchini A, Niesler B, Burnett M, Rappold GA . The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator . Human Molecular Genetics . 10 . 26 . 3083–91 . December 2001 . 11751690 . 10.1093/hmg/10.26.3083 . free .
• Ezquieta B, Cueva E, Oliver A, Gracia R . SHOX intragenic microsatellite analysis in patients with short stature . Journal of Pediatric Endocrinology & Metabolism . 15 . 2 . 139–48 . February 2002 . 11874178 . 10.1515/jpem.2002.15.2.139 . 46138078 .
• Ogata T, Muroya K, Sasaki G, Nishimura G, Kitoh H, Hattori T . SHOX nullizygosity and haploinsufficiency in a Japanese family: implication for the development of Turner skeletal features . The Journal of Clinical Endocrinology and Metabolism . 87 . 3 . 1390–4 . March 2002 . 11889214 . 10.1210/jcem.87.3.8348 . free .
• Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Bettendorf M, Heinrich U, Vlachopapadoupoulou E, Reinehr T, Onigata K, Ogata T . 6 . Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature . The Journal of Clinical Endocrinology and Metabolism . 87 . 3 . 1402–6 . March 2002 . 11889216 . 10.1210/jcem.87.3.8328 . free .
• Cormier-Daire V, Huber C, Munnich A . Allelic and nonallelic heterogeneity in dyschondrosteosis (Leri-Weill syndrome) . American Journal of Medical Genetics . 106 . 4 . 272–4 . 2002 . 11891678 . 10.1002/ajmg.10228 .
• May CA, Shone AC, Kalaydjieva L, Sajantila A, Jeffreys AJ . Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX . Nature Genetics . 31 . 3 . 272–5 . July 2002 . 12089524 . 10.1038/ng918 . 30559742 .

External links

• • GeneReview/NCBI/NIH/UW entry on SHOX-Related Haploinsufficiency Disorders

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Notes and References

1. Web site: SHOX - short stature homeobox - Genetics Home Reference . 2008-02-18 . 2005-09-01 . U.S. National Library of Medicine . 2007-10-12 . https://web.archive.org/web/20071012215043/http://ghr.nlm.nih.gov/gene=shox . dead .
2. Kanaka-Gantenbein C, Kitsiou S, Mavrou A, Stamoyannou L, Kolialexi A, Kekou K, Liakopoulou M, Chrousos G . 6 . Tall stature, insulin resistance, and disturbed behavior in a girl with the triple X syndrome harboring three SHOX genes: offspring of a father with mosaic Klinefelter syndrome but with two maternal X chromosomes . Hormone Research . 61 . 5 . 205–10 . 2004 . 14752208 . 10.1159/000076532 . 41958098 .
3. Raudsepp T, Chowdhary BP . The Eutherian Pseudoautosomal Region . english . Cytogenetic and Genome Research . 147 . 2–3 . 81–94 . 2015 . 26730606 . 10.1159/000443157 . free . 10576/22940 . free .