Discovery of a new ribosomopathy in humans that results in a lack of testis-determination or testicular regression

Institut Pasteur News Sep 16, 2019

Sex determination is the process whereby an organism becomes male or female. A multinational consortium, led by Institut Pasteur scientists, has made a breakthrough in understanding the genetics of sex determination in humans. They have discovered that DHX37, a gene highly conserved during evolution and until now only known for its role in ribosome biogenesis, is involved in both determining and maintaining the identity of testicular tissue. It is the first genetic cause to be identified for testicular regression. These findings open up new avenues for understanding the genetic origin of disorders of sex development (DSD). It will be published in the journal Genetics in Medicine and is available online.

DSDs are defined as congenital conditions with discordant development of chromosomal and gonadal/anatomical sex and cover a wide range of phenotypes that involve the endocrine and reproductive systems. Most of these conditions lead to sexual ambiguity at birth but some can only be diagnosed in adulthood. Testicular regression syndrome is a rare disease characterized by the uni- or bilateral absence of testes and has an embryonic origin. This syndrome affects roughly one in 2,000 boys. It represents approximately 32,700 births per year in the world and, in France represents about 180 births annually.

Using genomic approaches and in partnership with various universities and foreign hospitals, scientists from the Institut Pasteur have identified recurrent de novo mutations in individuals with DSD. These mutations are localized in highly conserved domains of gene DHX37, which codes for the protein DHX37.

Their findings show that 11% of patients with complete failure of testicular determination carry mutations in this gene. In addition, 25% of boys with testicular regression syndrome, which is also known as vanishing testis syndrome, carry pathogenic mutations in this gene. These figures point to mutations in DHX37 as a major cause of DSD.

"It is the first time that a genetic cause has been identified for testicular regression. The gene we have identified plays an essential role in testicular determination, and it is necessary to have a healthy gene for both testicle development and maintenance of testicular tissue. Our findings also prove that mutations in gene DHX37 are one of the most common causes of sex-reversal identified in humans." Dr Ken McElreavey, lead author of the paper and Head of the Human Developmental Genetics Unit at the Institut Pasteur.

DHX37 is a protein that has been highly conserved during evolution. It is known for being essential for biogenesis of the ribosome, and more specifically of its small subunit. "The relationship between protein DHX37 and the "pro-male" and "pro-female" regulation pathways involved in sex determination is completely unknown and it is a totlally unexpected discovery," explains Dr McElreavey.

This new data indicates that some DSDs should be added to the list of ribosomopathies. Ribosomopathies are human diseases associated with ribosome biogenesis or function. They are part of an emerging and, for the moment, poorly understood field of medicine. It is still unclear to the scientific community how the variants of proteins involved in ribosome biogenesis or function produce different and highly specific human phenotypes.

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