Two studies have found that certain disorders of the CAPRIN1 gene have important consequences for people. First, the research team showed that insufficient production of the CAPRIN1 protein in the brain can lead to developmental differences, including autism spectrum disorders, attention deficit hyperactivity disorder (ADHD) and of language. In addition, scientists identified a specific mutation in the CAPRIN1 gene (CAPRIN1P512L) that leads to abnormal protein buildup, resulting in unsteady gait and muscle weakness (myasthenia gravis). Both studies have been published in journals Brain and Cellular and Molecular Life Sciences.
This new knowledge has been made possible by exome analyses, in which scientists observe which genes are changed in a cell. The team also used the GeneMatcher database, a platform where researchers and doctors exchange information about gene mutations and the diseases associated with them.
The research team identified twelve patients who had mutations in the CAPRIN1 gene. In them, only half the amount of protein was produced. Lisa Pavinato, PhD student in the team of Professor Dr Alfredo Brusco at the University of Turin and holder of a DAAD scholarship with Professor Dr Brunhilde Wirth at the University of Cologne, discovered a link between the deficient production of the protein and some neurological impairments. Those affected all had speech impairments, 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 knocked out using CRISPR/Cas9 technology, creating the conditions from which affected individuals suffered. Cells with a CAPRIN1 mutation develop shortened processes and faulty circuitry that exhibit 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. Indeed, due to the faulty 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 disease with language failure, 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 position in the CAPRIN1 gene: an amino acid swap from proline to leucine at position 512. All three children have the same symptoms of early movement disorders (ataxia), speech motor disorders (dysarthria), memory disorders and myasthenia gravis. Andrea delle Vedove, a doctoral student in Professor Wirth’s team, has shown that this specific mutation leads to numerous protein clusters in neuronal cells similar to other neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease or ataxia. In addition, nerve cell activity was reduced. The CAPRIN1 studyP512L causes aberrant protein aggregation and is associated with early ataxia” appeared in 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 diagnoses. and more precise,” said Professor Dr Brunhilde Wirth, director of the Institute of Human Genetics at Cologne University Hospital, who led the studies with national and international teams.