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Paradox genders and malformed bones

Being a man has its difficulties – and these difficulties can also be biological. Despite having an X and a Y chromosome, carriers of SOX9 gene mutations are nevertheless at risk of developing female sex characteristics. A group of researchers led by Prof. Dr. Gerd Scherer at the University of Freiburg is investigating how this gene controls the correct development of a person’s gender. The researchers discovered the sex-related effect of the gene because SOX9 mutations can also lead to malformed bones.

Children with campomelic dysplasia have an abnormal curvature of the long bones (e.g., thigh bone) (Figure: Dr. Lehmann and Dr. Fiebig, Charité, Berlin)
Campomelic dysplasia is a disorder characterised by skeletal abnormalities. During foetal development, the cartilage tissue does not develop properly, leading to bowed and fragile long bones, e.g. the femur and the tibia. Only 10 per cent of all children with campomelic dysplasia (CD) survive longer than two years, the majority of them die of lung insufficiency before reaching the age of two. The oldest known CD patient is 54 years old; however she is only 1.07 m tall. Genetic examinations carried out around a decade ago showed that the disorder is caused by a mutation in the SOX9 gene. “Two thirds of all XY males with a mutated SOX9 gene are affected by another symptom,” said Prof. Dr. Gerd Scherer, head of the Department of Experimental Molecular Genetics at the Institute of Human Genetics and Anthropology at the University Hospital in Freiburg. “In these people, the mutation is also associated with sex reversal.”
People with a Y chromosome and a mutated SOX9 gene develop ovaries and vaginas rather than testes and penises. However, the sex organs are not fully functional because the ovaries do not produce female sex hormones. Although people with this mutation appear to be girls, they do not develop breasts or other secondary sex characteristics during puberty. This is a paradoxical situation. The CD patients are, in genetic terms, male, but are partially female in appearance. And all this is the result of one gene.

One gene controls testis development

“The discovery of SOX9 was interesting because, until 1994, we only knew of one gene that coded for the correct development of the male gonads,” said Scherer. This gene is SRY. It controls the production of testosterone in certain sex cells and induces the development of the males. The name SOX stands for SRY-related HMG box. SRY and SOX proteins possess a similar HMG box, a DNA-binding domain. These proteins are transcription factors and affect the transcription rate of a range of genes. SRY regulates only one target gene during testis development, i.e. SOX9, which however controls several different developmental processes, for example in the skeleton, intestines, pancreas and inner ear. Scherer and his group of researchers have been working on the function of this gene in testis since 1994.

The researchers are investigating a mouse line where they can switch off the SOX gene in certain cells and at particular points in time. The failure of the two SOX9 gene copies in the testis precursor tissue in male animals prior to the eleventh day of embryonic development leads to the development of ovaries instead of testes. In humans, this happens if one of the copies carries a mutation. Recent experiments with mice have revealed a number of unexpected developments. If the two copies are switched off after the fourteenth day of embryonic development, i.e. at the time when testis development has already started, then nothing happens – at least initially – and the sex organs develop apparently normally. “The effect only becomes visible after four to five months,” said Scherer explaining that the mice then suddenly become sterile. In other words, the testes no longer produce sperm. Therefore, SOX9 also seems to have a role to play after testis formation in order to maintain the genesis of germ cells. Scherer and his team are currently investigating the role of the gene in these processes.
The testes of male mice with two defective SOX9 gene copies do not develop normally and remain smaller (right column).
The testes of male mice with two defective SOX9 gene copies do not develop normally and remain smaller (right column). (Figure: Prof. Dr. Gerd Scherer)

Relief for parents

The research done by Scherer’s group will most likely be unable to contribute very much to the development of therapies for sex reversal. However, a precise knowledge of the SOX9 gene will have other important advantages. Campomelic dysplasia is always the result of new SOX9 mutations; defective SOX9 genes are not inherited because the majority of patients die before reaching sexual maturity. In couples who have already had a CD child, there is only a very slim probability – around 5 per cent - that they may have another CD child. The reason for this is a potential germline mosaic in the father or mother. In such cases, the SOX9 mutation is present in a precursor cell that continues to produce mutated germ cells. “For parents with this problem, we can offer prenatal diagnostics. The 95 per cent certainty that they will give birth to a healthy child is a huge relief for such parents,” said Scherer.

Scherer hopes to gain further insights into XY sex reversal, but his major aim is the clarification of the opposite phenomenon. In rare cases, XX sex reversal is also observed. In such cases, people with a female sex chromosome pair have a male appearance. The researchers have access to the family tree of a Kurdish family with some male members who are genetically female. This discrepancy is only identified at a much later stage: the people concerned have testes, but only very rudimentary ones that do not produce sperm. “The gene responsible for this situation is as yet unknown,” said Scherer who hopes that his research group will be able to discover the gene concerned.

mn – 13 Oct. 2008
© BIOPRO Baden-Württemberg GmbH
Further information:
Prof. Dr. rer. nat. Gerd Scherer
Institute of Human Genetics and Anthropology
Breisacher Str. 33
79106 Freiburg i. Br.
Tel.: +49 (0)761-270-7030
Fax: +49 (0)761-270-7041
E-mail: gerd.scherer@uniklinik-freiburg.de
Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/paradox-genders-and-malformed-bones