The Short Stature Homeobox SHOX Gene Effect On Overall Height

We continue in our quest to learn more about the disorders, illnesses, and possible ways a person can develop short stature. Today I learned that people who have the Short Stature Homeobox SHOX Gene can more easily develop into short stature. Let’s first figure out what exactly is this SHOX gene and what does it do.

From the National Institute of Health (NIH) website found HERE

What is the official name of the SHOX gene?

The official name of this gene is “short stature homeobox.” SHOX is the gene’s official symbol. The SHOX gene is also known by other names, listed below.

What is the normal function of the SHOX gene?

The SHOX gene provides instructions for making a protein that regulates the activity of other genes. On the basis of this role, the SHOX protein is called a transcription factor. The SHOX gene is part of a large family of homeobox genes, which act during early embryonic development to control the formation of many body structures. Specifically, the SHOX gene is essential for the development of the skeleton. It plays a particularly important role in the growth and maturation of bones in the arms and legs.

One copy of the SHOX gene is located on each of the sex chromosomes (the X and Y chromosomes) in an area called the pseudoautosomal region. Although many genes are unique to either the X or Y chromosome, genes in the pseudoautosomal region are present on both chromosomes. As a result, both females (who have two X chromosomes) and males (who have one X and one Y chromosome) have two functional copies of the SHOX gene in each cell.

Does the SHOX gene share characteristics with other genes?

The SHOX gene belongs to a family of genes called homeobox (homeoboxes). It also belongs to a family of genes called PAR (pseudoautosomal regions).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other.

How are changes in the SHOX gene related to health conditions?

Langer mesomelic dysplasia – caused by mutations in the SHOX gene
Langer mesomelic dysplasia results from genetic changes involving both copies of the SHOXgene in each cell. Deletions of this gene are the most common change responsible for this condition. Mutations in the SHOX gene can also cause the condition, as can deletions of nearby genetic material that normally helps regulate the gene’s activity. These changes greatly reduce or eliminate the amount of SHOX protein that is produced. A lack of this protein disrupts normal bone development and growth starting before birth. The resulting skeletal abnormalities include very short stature, extreme shortening of the long bones in the arms and legs (mesomelia), and an abnormality of the wrist and forearm bones known as Madelung deformity.
Léri-Weill dyschondrosteosis – caused by mutations in the SHOX gene
Léri-Weill dyschondrosteosis results from genetic changes involving one copy of the SHOX gene in each cell. Most commonly, this skeletal disorder is caused by a deletion of the SHOX gene. Other genetic changes that can cause the disorder include mutations in the SHOX gene or deletions of nearby genetic material that normally helps regulate the gene’s activity. These changes reduce the amount of SHOX protein that is produced. A shortage of this protein disrupts normal bone development and growth starting before birth. The resulting skeletal abnormalities are similar to those of Langer mesomelic dysplasia, although they tend to be less severe.
Turner syndrome – associated with the SHOX gene
Turner syndrome occurs when one normal X chromosome is present in a female’s cells and the other sex chromosome is missing or structurally altered. Because the SHOX gene is located on the sex chromosomes, most women with Turner syndrome have only one copy of the gene in each cell instead of the usual two copies. Loss of one copy of this gene reduces the amount of SHOX protein that is produced. A shortage of this protein likely contributes to the short stature and skeletal abnormalities (such as unusual rotation of the wrist and elbow joints) often seen in females with this condition.
other disorders – caused by mutations in the SHOX gene
    Deletions of the entire SHOX gene or mutations within or near the gene have been identified in some people with short stature. This short stature is usually described as idiopathic, which means it is not associated with the characteristic features of a disease or syndrome. However, some people with short stature and changes in the SHOX gene have been found to have subtle skeletal abnormalities.

Where is the SHOX gene located?

Cytogenetic Location: Xp22.33;Yp11.3

Molecular Location on the X chromosome and the Y chromosome: base pairs 535,078 to 570,145

The SHOX gene is located on the short (p) arm of the X chromosome at position 22.33 ; on the short (p) arm of the Y chromosome at position 11.3.

The SHOX gene is located on the short (p) arm of the X chromosome at position 22.33 ; on the short (p) arm of the Y chromosome at position 11.3.

More precisely, the SHOX gene is located from base pair 535,078 to base pair 570,145 on the X chromosome and the Y chromosome.

What other names do people use for the SHOX gene or gene products?

  • GCFX
  • growth control factor, X-linked
  • PHOG
  • pseudoautosomal homeobox-containing osteogenic gene
  • SS

From the website Science 2.0 (Resource) I wanted to post another article on what the functions of the gene are. As always, I will highlight the parts which are the most important and applicable to our height increase endeavors

Not Just The Gene – Abnormal SHOX Regulation Implicated In Short Stature And Leri-Weill Syndrome

By News Staff | August 25th 2009 12:00 AM |
The so-called SHOX gene (short stature homeobox gene) is responsible for the normal growth of bones and is often mutated in short-stature patients. Short stature is considered when final height of an individual is no more than 160 cm (men) or 150 cm (women).

Researchers in Heidelberg have now discovered that sequences of genetic material on the X and Y chromosome that regulate this gene are also crucial for growth in children.

These gene regulators determine how frequently a gene is copied, thus how effective it is. In many cases, the mutation of one regulatory sequence of the homeobox transcription factor gene SHOX is sufficient to give rise to the full-blown syndrome. Professor Gudrun Rappold, Director of the Department of Human Molecular Genetics at Heidelberg University Hospital and her team of researchers have published their results in the Journal of Medical Genetics, available as an open access article at the link below.

These results could open up new possibilities for diagnosing the cause of short stature and initiating treatment before it is too late.

There are many causes of short stature, e.g. hormone disorders, malnutrition, chronic disease, or a genetic disorder. If, in addition to short stature, other symptoms such as short forearms and lower legs or other bone malformations also occur, it is considered a syndrome. However, often no exact cause can be determined and other typical features are lacking – this is then known as idiopathic short stature.

SHOX gene mutation is frequently the cause of short stature 

Professor Rappold’s team discovered back in 2007 that in over 4 percent of children with idiopathic short stature, the trigger for the disorder was a mutation in the SHOX gene. This gene lies on the X chromosome and is responsible for growth in the epiphyseal plate, where the long bones of the arms and legs grow in length. After puberty, epiphyseal fusion takes place. When there is a mutation of the SHOX gene, patients reach a height up to 20 cm less than expected. Up to about 15 cm can be regained if the disease is diagnosed early enough and treated with growth hormones. The SHOX gene is involved in various other syndromes with growth disorders (Léri-Weill, Langer, Ullrich-Turner syndrome).

The researchers’ latest studies show that not only the gene itself, but its regulators as well can be crucial for developing the disease. Regulatory sequences ensure that the respective gene is copied more or less frequently and thus is more or less effective.

The researchers in Heidelberg examined the genetic material from a total of 893 subjects. About 5 percent of the patients with idiopathic short stature and 80 percent of the patients with Léri-Weill syndrome had mutations in the segment either including or around the SHOX gene. Some patients had an intact SHOX gene but an unexpectedly high number of mutations in its enhancer sequences: for 26 percent of patients with SHOX deficiency and idiopathic short stature and for 45 percent of patients with SHOX deficiency and Léri-Weill syndrome, the disease could be attributed solely to a genetic mutation of the enhancer sequence. “The astounding thing is that this enhancer mutation is quite far away from the affected gene and yet it still leads to the exact same clinical symptoms as a mutation in the gene itself,” says Professor Rappold.

Genes that are responsible for growth and development are needed more or less frequently in different phases of growth. In these genes in particular, mutations in the regulatory sequences can be the decisive factor for illness. The researchers hope that their results will give them a better understanding of the causes of the disease and allow them to optimize the diagnostic possibilities for patients with SHOX gene mutations.

“Patients who suffer from their short stature often have a great need to be able to name the cause. Even if it is not possible to treat the cause, patients with mutations of the SHOX gene can benefit from a treatment of the symptoms with growth hormones,” explains Professor Rappold.

Article: Jianjun Chen, Gabriele Wildhardt, Zilin Zhong, Ralph Roeth, Birgit Weiss, Daniela Steinberger, Jochen Decker, Werner F Blum and Gudrun A Rappold, ‘Enhancer mutations of the SHOX gene as a frequent cause of short stature – the essential role of a 250 kb downstream regulatory domain’, J Med Genet. Published Online First: 2 July 2009. OPEN ACCESS.   doi:10.1136/jmg.2009.067785

Me: So clearly this is a big major breakthrough in understanding at least which genes hav a profound affect on our over height. What amazed me was that if there is a mutation of the SHOX gene, the patients can be up to 8 inches shorter than expected. However, if one can realize and diagnose the problem early enough, growth hormone treatments can help get back around 6 inches of height. Now, this is great news for people , especially children, who have been on the lower percentile in the height and growth rate range while they are still developing.  


Turner syndrome presented with tall stature due to overdosage of the SHOX gene.

“Turner syndrome is one of the most common chromosomal disorders. It is caused by numerical or structural abnormalities of the X chromosome and results in short stature and gonadal dysgenesis. The short stature arises from haploinsufficiency of the SHOX gene, whereas overdosage contributes to tall stature. This report describes the first Korean case of Turner syndrome with tall stature caused by SHOX overdosage. The patient presented with primary amenorrhea and hypergonadotropic hypogonadism at the age of 17 years. Estrogen replacement therapy was initiated at that time. She displayed tall stature from childhood, with normal growth velocity, and reached a final height of 190 cm (standard deviation score, 4.3) at the age of 30 years. Her karyotype was 46,X, psu idic(X)(q21.2), representing partial monosomy of Xq and partial trisomy of Xp. Analysis by multiplex ligation-dependent probe amplification detected a duplication at Xp22.3-Xp22.2, encompassing the PPP2R3 gene near the 5′-end of the SHOX gene through the FANCD gene at Xp22.2.”

” The SHOX gene is expressed in limbs, pharyngeal arches, osteogenic cells, and bone marrow fibroblasts, and is involved in skeletal growth and development. The loss of the SHOX gene therefore leads to short stature and various skeletal abnormalities, such as short metacarpals, high-arched palate, cubitus valgus, Madelung deformity, and mesomelia. The SHOX gene is expressed on both the inactive X chromosome and the active X or Y chromosome, thereby escaping from X chromosome inactivation. According to the altered SHOX dosage, haploinsufficiency causes short stature, while overdosage contributes to tall stature.”

“She did not menstruate until she was 30 years old and still presented with breast and pubic hair at Tanner stage 3.”

“SHOX overdosage and gonadal dysgenesis[ progressive loss of germ cells on the developing gonads of an embryo] contribute to sustained growth, with constant height velocity from infancy to adolescence”

“This patient continued to grow after 18 years of age, despite estrogen replacement therapy lasting 10 years, suggesting that SHOX overdosage surpasses the skeletal maturing effect of estrogen. However, other deleted genes on Xq or duplicated genes on Xp could have contributed to the tall stature of our patient.”

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