15 December 2016
A gene previously implicated in swollen kidneys also contributes to an autism syndrome, a finding that could help with diagnosis of both conditions.
The gene is known as teashirt zinc-finger homeobox family member 3, or TSHZ3. Its discoverer, Laurent Fasano, first described the fruit fly version of this gene 25 years ago. Fasano and his colleagues at France’s Developmental Biology Institute of Marseille have since shown in mice and humans that TSHZ3 plays pivotal roles in the differentiation of the smooth muscles that help transport urine from the kidney to the bladder and in the development of neurons in the hindbrain that regulate breathing.
A curious clinical observation led the researchers to investigate yet another function of TSHZ3.
Joris Andrieux, a medical geneticist at France’s Jeanne de Flandre Hospital in Lille, had a patient who was missing part of the TSHZ3 gene. This child exhibited developmental delays, intellectual disabilities and other autistic features, in addition to kidney tract problems. Because of the genetic similarity, Fasano and his colleague Xavier Caubit decided to take a closer look at their mice for signs of neurocognitive deficits. Sure enough, the animals with mutations in the mouse version of TSHZ3 displayed behavioural abnormalities consistent with an autism spectrum disorder (ASD).
Andrieux then helped Fasano reach out to physicians around the world to see if anyone knew of other patients who had both autism and kidney problems owing to a TSHZ3 mutation. He found such cases in France, Sweden, the United Kingdom and the United States. “This study was only possible because scientists and clinicians with different and complementary expertise have decided to share their data and the result is just amazing,” Fasano says.
Back in the laboratory, Fasano and his research team dug deeper into the molecular mechanisms by which mutations in TSHZ3 trigger an autism syndrome. They looked at genes expressed in a developing fetal human brain, and found 34 that contribute to ASD that were also highly expressed alongside TSHZ3. Furthermore, they showed that the TSHZ3 gene itself was most active in deep layers of the brain’s neocortex known to contribute to the development of autism. The researchers confirmed these findings in Fasano’s mouse models.
These mice with TSHZ3 mutations can now be used to look for new treatments for ASD. Moreover, Fasano notes, children who have kidney issues or signs of an autism syndrome can now have their TSHZ3 gene status tested to see whether they need to be screened for other health problems.
Caubit, X., Gubellini, P., Andrieux, J., Roubertoux, P.L., Metwaly, M. et al. TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nature Genetics. (2016).| article