nearly 60 years ago, a researcher H Turner had pointed out that females lacking one of the two x chromosomes, display a variety of abnormalities. The abnormalities include below-average height, poor development of sexual characteristics and other less serious anatomical signs. The defect in sexual development is caused by a hormonal deficiency resulting from malfunctioning of the ovaries. All the symptoms are known as Turner's syndrome and are manifested by one in 4,000 to 5,000 females.
But the growth defect remained unexplained because girls with the chromosomal defect are found to have normal levels of thyroid hormones. Turner's syndrome was still not clear as one of the two x chromosomes in each cell of a female mammal is randomly chosen to be permanently inactive. So how could its absence make any difference?
Recently, Ergole Rao and his colleagues of the Institute of Human Genetics, Heidelberg University, Germany, claim that they have solved these problems. They say that although inactivation of x chromosome occurs in female mammals, a small region at the tip of the x chromosome escapes inactivation. This is about 2.6 million bases in size and carries genes that are shared or paired with genes in the male y chromosome which is also largely inactive. So the complications are not due to the loss of a chromosome that is inactive. But it is due to the loss of a specific region that is normally active ( Nature Genetics , Vol 16, No 1).
Unlike most genes in other organisms, the putative Turner's syndrome gene that leads to short stature when it is absent, needs to be present in two copies; one copy by itself is insufficient to do the job. In other words, it is a dosage defect that is responsible for this aspect of the syndrome. Out of two genes that express a similar function, if one gene is absent then the other could not execute the function. This is known as dosage defect.
The researchers also investigated the possible gene whose absence might lead to the growth defect. It was discovered that persons with xy chromosomal constitution, who ought to develop as males, but who lacked the paired region on the y chromosome, also exhibited features of Turner's syndrome. Such individuals developed just like females because the missing portion on the y chromosome included the region necessary for male sexual development. This finding backed the idea that the paired region at the tip of the x chromosome might be involved in the growth defect.
Rao and his colleagues later focused on the sub-region of dna that was about 700,000 bases in size. They examined the dna from 36 individuals, both males and females, who exhibited both short stature and an abnormal sex chromosome. The study confirmed the presence of a single gene, called shox . The same shox gene encodes two proteins, named shox a and shax b. These proteins can act on dna as transcription factors and are found in a variety of foetal and adult tissues. As expected, shox can be detected whenever there is a y chromosome, and an active or an inactive x chromosome.
How confident can one be that shox is the Turner syndrome gene that affects stature? Besides the indirect evidence already mentioned, the same group has accidentally discovered a single family in which short stature is associated with a mutated version of shox . The evidence is not conclusive because individuals with short stature who lack shox also display other complex chromosomal abnormalities. In the affected family, some family members who lack the shox mutation are almost as short as those who carry it. At present, the results look promising but further developments are awaited. The findings may lead to new therapies for growth disorders.
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