Function of the SHOX Gene and Disorders caused by SHOX Gene Mutation

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The SHOX Gene

The SHOX gene is present on both the X and Y sex chromosomes, in a location called the pseudoautosomal region. This region is so-called because it is comprised of homologous sequences which are present on both sex chromosomes. (In contrast, the remaining genes on the sex chromosomes are non-homologous.) Normal males and females therefore have two copies of the genes in the pseudoautosomal region.

The primary function of the pseudoautosomal region is not, however, to contain genetic information, but to provide a “reference point” for the sex chromosomes to pair up during male meiosis. This is necessary because in male meiosis, an X and Y chromosome must line up together, and the presence of the pseudoautosomal region helps this happen with greater accuracy.

Disorders caused by SHOX Gene Mutation

The most common genetic disorder associated with SHOX gene mutation is Turner syndrome. This condition develops in females who have only one functional X chromosome. As a result, women with this condition have only one SHOX gene, and therefore produce only half the normal amount of SHOX protein.

The current theory on the development of Turner syndrome is that this condition develops due to a shortage of SHOX protein, resulting in skeletal abnormalities and short stature.

Leri-Weill dyschondrosteosis is another genetic disorder caused by SHOX mutation. This disorder is generally the result of point mutations or deletions in one copy of the SHOX gene. This disorder is characterized by short forearm and lower leg bones, and abnormalities of the wrist bones. Langer mesomelic dysplasia is a similar disorder with more severe symptoms. This disorder develops in people with two mutated copies of the SHOX gene.

Causes of SHOX Gene Mutation

SHOX gene mutations can be of several different types, including point mutations, as well as deletions of various sizes. In Turner syndrome, the cause is deletion of not only the SHOX gene, but the absence of an entire X chromosome. This condition therefore causes other symptoms in addition to delayed or absent growth development, due to the absence of other genes.

In familial Leri-Weill dyschondrosteosis, both point mutations and deletions have been found in family groups. These include large deletions of multiple exons (coding regions) in the SHOX gene, as well as small deletions in a single exon. As well, several types of point mutation, including frameshift and missense mutations, have been noted (Falcinelli et. al.). It should be noted that not all instances of this disorder in family groups are caused by SHOX gene mutation. In one study, mutations of the gene were found in only 62% of the families studied (Falcinelli et. al.).

SHOX gene mutations are relatively common in certain short stature genetic disorders of familial origin, and are also a cause of a small percentage of cases of idiopathic short stature (idiopathic short stature conditions are those with no known cause). In one study of 900 children with idiopathic short stature, SHOX gene mutations were detected in only 2.4% of cases. (Gudrun et. al.) The same study found that deletion was the most common mutation leading to short stature disorder.


C Falcinelli, L Iughetti, A Percesepe, G Calabrese, F Chiarelli, M Cisternino, L De Sanctis, I Pucarelli, G Radetti, M Wasniewska, G Weber, L Stuppia, S Bernasconi, A Forabosco. SHOX point mutations and deletions in Leri-Weill dyschondrosteosis. J Med Genet 2002;39. (Full text online version requires free registration.)

Gudrun A. Rappold, Maki Fukami, Beate Niesler, Simone Schiller, Walter Zumkeller, Markus Bettendorf, Udo Heinrich, Elpis Vlachopapadoupoulou, Thomas Reinehr, Kazumichi Onigata and Tsutomu Ogata. 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 & Metabolism Vol. 87, No. 3 1402-1406.

U.S. National Library of Medicine Genetics Home Reference: SHOX