Identification of a new gene involved in pontocerebellar hypoplasia
Representative sections of brain MRIs for affected individuals with TBC1D23 mutations. First row, sagittal images in four different individuals showing pontocerebellar hypoplasia (PCH) (white arrows); hypoplasia of the corpus callosum (F1-II-3, double arrowheads) and agenesis of the corpus callosum (F1 II-2 and F2 II-4, arrowheads). Second row, axial sections showing a small, butterfly-shaped cerebellum (red asterisks).
Am J Hum Genet Sept. 7, 2017
Aug. 17, 2017
Pontocerebellar hypoplasia represents a group of clinically and genetically diverse pathologies characterized by the lack of development of pons and cerebellum. Based on clinical and molecular features, there are currently ten described subtypes of pontocerebellar hypoplasia. Despite the identification of mutations in 13 genes to date, more than 25% of cases remain unexplained. Jamel Chelly's team at the IGBMC has uncovered a new gene involved in pontocerebellar hypoplasia. This work is published on August 17 in The American Journal of Human Genetics.
Although clinical features vary widely, pontocerebellar hypoplasia is generally associated with intellectual disability. In most cases, the disease is severe and the lifespan often limited.
In this study, researchers of Jamel Chelly’s team show the involvement of mutations in the TBC1D23 gene in children from three families with clinical signs of the disease. Magnetic resonance imaging (MRI) reveals a lack of development of the brain stem with a small butterfly-shaped cerebellum, a microcephaly and anomalies of the corpus callosum. Patients present with motor and coordination disorders, mental retardation more or less pronounced, behavioral disorders as well as autistic traits.
The researchers also demonstrate that positioning of neurons during the development of the cortex as well as the formation of nerve prolongations are affected when TBC1D23 expression is downregulated. Dysfunction of this gene, which encodes a protein involved in intracellular transport, disrupts this process, which would contribute to developmental abnormalities and neurological disorders.
These results provide a better understanding of the mechanisms involved in the development of the central nervous system and reveal the implication of the TBC1D23 gene in pontocerebellar hypoplasia. This gene should therefore be screened in individuals with syndromic pontocerebellar hypoplasia.
This study is funded by the ANR, the Rare Diseases Foundation and the Foundation for Medical Research and IdEx Strasbourg.