Researchers at the University of California, San Diego School of Medicine have identified a genetic cause for a form of pediatric brain malformation involving the cerebellum.
Future research based on these findings could lead to ways of preventing or treating children with Joubert Syndrome Related Disorder (JSRD.)
The research team, directed by Joseph Gleeson, M.D., Director of the Neurogenetics Laboratory at the UCSD School of Medicine and associate professor in the Department of Neurosciences, have identified a new gene that, when mutated, leads to JSRD. Their findings are published on-line in the journal Nature Genetics.
JSRD is a group of neurodevelopmental syndromes marked by absence of the middle part of the cerebellum called the vermis, along with features including poor balance, jerky eye movements, mental retardation and autism. The most consistent feature seen in children affected with JSRD is a striking finding on brain MRI called the "molar-tooth sign," in which the base of the brain takes on the appearance of a tooth. A subset of JSRD patients also displays disease in other body organs including the retina, kidneys and liver.
The discovery of the new gene linked to JSRD was found in collaboration with scientists at the Mendel Institute in Rome, under the direction of Enza Maria Valente. The researchers studied a large family from Sardinia, Italy, with several members exhibiting the disease. Within the family, in which the parents were second cousins, the scientists discovered a new genetic interval and the presence of the CEP290 (Centrosome-associated protein 290) gene. The research teams identified inactivating mutations in CEP290 in this family and mutations were also identified in families with similar diseases in Turkey, the Palestinian region of Israel and Pakistan. This gene has not previously been implicated in human disease, and encodes a novel protein, previously identified as a centrosomal-associated protein, but with unknown function.
Once the mutations were identified, the group set out to understand the role of the protein in development of the human cerebellum. They found that the gene was produced predominantly in the population of neurons in the brain called cerebellar granule neurons. They also discovered specific protein targets suggesting that the gene may control cell division in the cerebellum during the human development, which would account for the cerebellar defect seen in these patients.