Discovery of a genetic mutation that causes language

image: Representative images of neuronal rosettes derived from control samples and CAPRIN1 +/- cells. CAPRIN1 (magenta) protein could be easily detected in these structures.
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Credit: Brunhilde Wirth, University of Cologne

Two studies revealed that some CAPRIN1 gene disorders have significant consequences for people. First, the research team showed that insufficient production of the CAPRIN1 protein in the brain can lead to impairments, including autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and speech disorders. Furthermore, the scientists identified a specific mutation in the CAPRIN1 gene (CAPRIN1P512L) which leads to an abnormal accumulation of proteins, causing unstable gait and muscle weakness (myasthenia). The two studies were published in journals brain And Cellular and Molecular Life Sciences.

These new insights were made possible by exome analyzes, in which scientists observe which genes are altered in a cell. The team also used the GeneMatcher database, a platform on which researchers and doctors exchange information on mutations in genes and associated diseases.

The research team identified twelve patients who had mutations in the CAPRIN1 gene. Only half the amount of protein was produced in them. Lisa Pavinato, PhD researcher in the team of Professor Alfredo Brusco at the University of Turin and holder of a DAAD scholarship with Professor Brunhilde Wirth at the University of Cologne, has discovered a connection between deficient production of the protein and some neurological disorders . Those affected all had speech disorders, 82% had ADHD, and 67% had autism spectrum disorders and other neurodevelopmental disorders. The function of CAPRIN1 was confirmed in laboratory experiments with human-induced pluripotent stem cells in which the CAPRIN1 gene was deactivated using CRISPR / Cas9 technology, creating the conditions that affected individuals suffered. Cells with a CAPRIN1 mutation develop shortened processes and faulty circuits that show reduced electrical activity compared to healthy neurons without the mutation. In contrast, control neurons without the CAPRIN1 mutation form long processes, developing into complex networks. In addition, the team also discovered changes in translation, one of the most important cellular processes for error-free cell formation and function. In fact, due to the incorrect translation, the mutant neurons began to degenerate and form clumps after a few days. The results of this research were published in the article ‘CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with speech impairment, ADHD and ASD’ in brain.

In the second study, GeneMatcher was used to identify three children from different families with a newly developed point mutation at a specific location in the CAPRIN1 gene: an amino acid exchange from proline to leucine at location 512. All three children show the same symptoms of early onset movement disorders (ataxia), impaired speech motor skills (dysarthria), memory impairment and myasthenia. Andrea delle Vedove, PhD researcher in Professor Wirth’s team, has shown that this specific mutation leads to many protein clumps in neuronal cells similar to other neurodegenerative diseases such as Parkinson’s, Alzheimer’s or ataxia. Furthermore, the activity of the nerve cells was reduced. The ‘CAPRIN1P512L causes aberrant protein aggregation and is associated with early onset ataxia Cellular and Molecular Life Sciences.

“The new research findings are important not only for affected patients and their families, who often spend years searching for answers to understand the cause of their disease, but also for doctors, who can now make faster and more accurate diagnoses. “said Professor Dr Brunhilde Wirth, director of the Institute of Human Genetics at the University Hospital of Cologne, who conducted the studies together with national and international teams.

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