Genes discovered for brain pathway that triggers onset of adulthood.
Four families from Turkey with a genetic disorder that prevents children developing normally into adults have helped geneticists to track down genes which trigger puberty.
The researchers, from Cukurova University, Turkey and the University of Cambridge, UK, have shown that the families have mutations in the genes responsible for either a peptide found in the brain, neurokinin B, or its receptor. Eight children from the four families have a condition called normosmic idiopathic hypogonadotropic hypogonadism (nIHH), in which they fail to develop normal secondary sexual characteristics in adolescence. Males have a small penis and undescended testes but are otherwise physically and mentally normal.
The study, published in Nature Genetics1, suggests that neurokinin B is key in stimulating the production of gonadotropin releasing hormone (GnRH) by the hypothalamus. This causes another part of the brain, the pituitary gland, to release two hormones — luteinising and follicle stimulating hormones — that trigger the synthesis of various sex hormones in the testes or ovaries.
Timing is everything
Kemal Topaloglu and colleagues analysed the genomes of both affected and unaffected children within the four families and located two mutations in the TAC3 and TACR3 genes, known to encode neurokinin B or its receptor molecule. They also introduced the receptor gene into cultured cells and found that it allowed calcium ions to flow into cells — a process that might help to trigger hormone production by the hypothalamus. Cells with the mutant gene didn't see a similar influx of calcium.
Neurokinin B is the second signalling protein found to have a role in regulating GnRH production. In 2003 American and French teams independently discovered that mutations in the peptide kisspeptin and its receptor GPR54 prevent normal development during puberty2,3 But that mutation didn't explain all cases of nIHH, and various groups began looking for a second signalling factor.
"The cells responsible for GnRH production act like a clock in sending out pulses of hormone which go down to the pituitary,' explains Stephen O'Rahilly, director of the Institute of Metabolic Sciences at the University of Cambridge, UK. "But a continuous stream of hormone actually switches off the production of hormones further down the chain. As the timing is so crucial, it is not surprising that you will have several different signalling factors to fine tune the process."
Children affected by nIHH can be treated with hormones to undergo the normal changes of puberty. Indeed, Kemal Topaloglu, lead author of the paper, was working in Cambridge before returning to Turkey to treat the children described in the paper. Theirs is a very rare condition resulting from high rates of intermarriage in isolated rural communities. But problems with premature or delayed puberty are much more common, affecting perhaps 1 in 10,000 children.
Gaining a better understanding of the processes that trigger puberty will help in developing new treatments for these children. The findings may also provide key information for controlling other hormone-regulated diseases.
However, neurokinin B is expressed by various tissues around the human body, and it may be difficult to develop treatments that hit specific targets without disrupting other organs.
"Key issues to be examined now are whether it is neurokinin B acting in the brain or elsewhere in the body that is critical for reproduction, and how this could be used for the safe manipulation of fertility in humans," warns Allan Herbison, head of the department of physiology at the University of Otago in Dunedin, New Zealand. "Unfortunately, neurokinin B is part of a family of peptides involved in a huge variety of physiological processes."
Topaloglu, A.K., et al. Nature Genetics DOI: 10.1038/ng.306
Seminara, S. B., et al. N. Engl. J. Med,.349, 1614-1627, (2003)
De Roux, N.; et al. Proc. Natl. Acad. Sci. USA 100 10972-10976, (2003)
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Bonner, J. Kickstarting puberty. Nature (2008). https://doi.org/10.1038/news.2008.1300