Massachusetts General Hospital (MGH) clinical researchers and their collaborators from the University of California, Irvine said that they had found defects in a gene called PROK2 (prokineticin 2) in human siblings, who were suffering from two different forms of infertility.
In a previous study, the UC Irvine team had reported that mice lacking PROK2 had abnormal olfactory structures and disrupted circadian rhythm.
"We have demonstrated that PROK2 signalling is a novel pathway that is critical to the development of neurons that control the reproductive system, findings that should enable better understanding of human reproduction," says Dr. Nelly Pitteloud, MD of the Reproductive Endocrine Unit in the MGH Department of Medicine, who is the lead author of the study to be published in the Proceedings of the National Academy of Sciences.
The researchers investigated into the genetic basis of idiopathic hypogonadotropic hypogonadism (IHH), a rare condition in which puberty does not take place naturally. They revealed that IHH could occur when a structure in the brain called the hypothalamus fails to develop neurons that secrete gonadotropin-releasing hormone (GnRH), a major controller of the reproductive system.
Their study involved 100 participants50 with Kallmann syndrome, a form of IHH that involves lack of both reproductive development and a sense of smell, and half with normal sense of smell. The researchers found that three members from the same family in Portugal, two brothers and a sister, had identical defects in both copies of the PROK2 gene.
Upon further study of the same family, the researchers found another brother with mutation in only one PROK2 copy and a normal reproductive history. Five siblings of those individuals had died in infancy.
While the two affected brothers had Kallmann syndrome, their affected sister had a normal sense of smell but did not experience normal puberty. "Until recently, IHH with a normal sense of smell and Kallmann syndrome with no sense of smell had been considered two distinct clinical entities," says Pitteloud, an assistant professor of Medicine at Harvard Medical School.
"We now have described several kindreds in which different family members exhibit both syndromes yet harbour the identical mutation. So, it looks like additional gene defects or environmental cues modify how these syndromes develop in affected families," added the researcher.
Dr. Qun-Yong Zhou, a professor of Pharmacology in its School of Medicine at UC Irvine, made fundamental contributions to the understanding of the neurobiological functions of prokineticin and its receptors, with the help of his colleagues. His team found that in mice lacking functional copies of PROK2 gene, the reproductive defect was due to the abnormal migration of neurons that secrete GnRH.
"Many recessive human genetic disorders, particularly the ones that have associated infertility symptom, are very difficult or almost infeasible to investigate using genetic analysis. The current study provides an elegant example how mouse studies can pinpoint the underlying genetic cause for human IHH disorders," says Dr. Zhou.