A condition characterized by delayed or absent puberty and an impaired since of smell has been linked to a molecule that plays a key role in the formation of blood vessels and brain wiring. This was published in a new Journal of Clinical Investigation study published on Monday.
Known as Kallmann Syndrome, the condition is a type of hypogonadotropic hypogonadism that affects one out of every 10,000 to 86,000 people, according to the National Institutes for Health. Now, researchers from University College London and the University of Milan report that they may have found the genetic fault that causes this disorder to occur.
Studying a pair of brothers afflicted with Kallman Syndrome, they found that there was a flaw that was preventing the molecule SEMA3E from functioning correctly. SEMA3E has been found to protect the nerve cells that regulate sexual reproduction, and those nerve cells grow in the nose of developing fetuses before migrating to the brain.
Once they reach the brain, they produce gonadotropin-releasing hormone (GnRH), a substance that is required to stimulate puberty. The authors found that these GnRH-producing nerve cells could not survive the migration unless SEMA3E was there to protect them along the way.
SEMA3E is the key
As the UCL and University of Milan teams used a combination of exome sequencing and computational modeling to detect the mutation in the two brothers, and then went on to verify the effect in tissue cultures as well as in mice that lacked SEMA3E.
Their study, the authors wrote, “has uncovered a hitherto unknown role for SEMA3E as a neurotrophic factor” essential for GnRH neuron development. Furthermore, they said that their findings will “prompt direct SEMA3E mutation screening” in Kallmann Syndrome patients, lead to increased use of exome sequencing to study the genetics behind the condition, and serve as a launching point for research into GnRH neuron development and deficiency.
“By combining clinical and laboratory approaches, we were able to go far beyond simply identifying ‘candidate’ genes that might be linked to a given disease,” senior author Professor Christiana Ruhrberg said. “Many genetic studies rely on statistical correlations from thousands of patients, making it difficult to study rare diseases such as Kallmann Syndrome.”
“We managed to confirm genetic causes using blood samples from just two brothers with the condition, born two years apart,” she added. “By recreating the mutations and testing them in neuronal cells in tissue culture, and by examining mice born without the genes that were mutated in both brothers, we found concrete evidence showing how these mutations actually cause the condition.”