CAPRIN1: one gene - different mutations - two distinct disorder

The first study with the title “CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD” has been published in Brain -  https://doi.org/10.1093/brain/awac278
The second study with the title "CAPRIN1^P512L causes aberrant protein aggregation and associates with early-onset ataxia" has been published in Cell Mol Life Sci Cell Mol Life Sci. - https://doi.org/10.1007/s00018-022-04544-3.

“The findings of the two studies will have important implications not only for all the patients and for their families, who now know the cause of their condition, but also for medical doctors, who can directly provide faster and more accurate responses. Moreover, it is an example of how new technologies and cooperativity proves to be an effective strategy in order to unravel complex puzzles”, Prof. Brunhilde Wirth, director of the Institute of Human Genetics at the Medical Faculty of the University of Cologne, the Center for Rare Disorders at the University Hospital of Cologne and the Center for Molecular Medicine Cologne (CMMC) comments.

More than every other organ, the human brain undergoes an astounding maturation during the first years of life. This process shapes a great variety of skills, ranging from the “simple” action of walking to the complex ability of communicating. Genetic factors are key drivers of this progress and often play a central role in retaining the acquired competences. Indeed, genetic mutations are the cause of many neurodevelopmental and neurodegenerative disorders.

Using exome sequencing and GeneMatcher, the research groups of Prof. Wirth and Prof. Brusco were able to associate two novel disorders to mutations in CAPRIN1. CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types.

Lisa Pavinato, PhD student of Prof. Brusco, gathered a cohort of 12 individuals suffering from a neurodevelopmental disorder, mainly characterized by language impairment and intellectual disability. They carried CAPRIN1 variants leading to its reduced expression. In parallel, together with collaborators, the research group of Prof. Wirth identified an extremely rare and specific CAPRIN1 mutation in two young individuals affected by a neurodegenerative disease, causing unstable gait and muscle weakness. Andrea Delle Vedove, PhD student in Prof. Wirth’s lab, demonstrated that this CAPRIN1P512L mutation induces an aberrant protein aggregation and accumulation of ataxia- and neurodegeneration-related proteins.

Thanks to a 10-months DAAD scholarship, Lisa joined the research group of Prof. Wirth, where Andrea generated via CRISPR/Cas9 technology inducible pluripotent stem cells carrying the same mutations as in the patients. In order to investigate the disease mechanisms in the affected cell type, they differentiated these cells into neurons.

In cells expressing low CAPRIN1 levels, Lisa observed a reduced organization and electric activity. Moreover, these cells suffered increased oxidative stress and cellular degeneration. She also demonstrated alterations of protein translation and calcium signaling, important processes for the cell physiology.

On the other side, Andrea investigated cells harboring the CAPRIN1P512L mutation. He could detect reduced neuronal activity, and he additionally observed an alteration of the neuronal stress response, reported in other neurodegenerative disorders. These findings demonstrated a distinct pathological mechanism and explained the difference between the two phenotypes.

In conclusion, this work has important implications not only for all the patients and for their families, who now know the cause of their condition, but also for medical doctors, who can directly provide faster and more accurate responses. Moreover, it is an example of how new technologies and cooperativity proves to be an effective strategy in order to unravel complex puzzles.

Scientific contact:
Prof. Dr. Brunhilde Wirth
Director - Institute of Human Genetics
affiliated with the Center for Rare Disorders at the University Hospital of Cologne and
the Center for Molecular Medicine Cologne, University of Cologne

E-Mail: brundhilde.wirth@uni-koeln.de

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Original publications:
CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.
Lisa Pavinato, Andrea Delle Vedove, Diana Carli, Marta Ferrero,Silvia Carestiato, Jennifer L. Howe, Emanuele Agolini, Domenico A. Coviello, Ingrid van de Laar, Ping Yee Billie Au, Eleonora Di Gregorio, Alessandra Fabbiani, Susanna Croci, Maria Antonietta Mencarelli, Lucia P. Bruno, Alessandra Renieri, Danai Veltra, Christalena Sofocleous, Laurence Faivre, Benoit Mazel, Hana Safraou, Anne-Sophie Denommé-Pichon, Marjon A. van Slegtenhorst, Noor Giesbertz, Richard H. van Jaarsveld, Anna Childers, R. Curtis Rogers, Antonio Novelli, Silvia De Rubeis, Joseph D. Buxbaum, Stephen W. Scherer, Giovanni Battista Ferrero, Brunhilde Wirth ^# and Alfredo Brusco^#
Brain (2022) - https://doi.org/10.1093/brain/awac278
# These authors contributed equally to this work

CAPRIN1^P512L causes aberrant protein aggregation and associates with early-onset ataxia.
A Delle Vedove, J Natarajan, G Zanni, M Eckenweiler, Muiños Bühl, M Storbeck, J Guillén Boixet, S Barresi, S Pizzi, I Hölker, F Körber, TM Franzmann, ES Bertini, J Kirschner, S Alberti, M Tartaglia, B Wirth.
Cell Mol Life Sci. (2022) - https://doi.org/10.1007/s00018-022-04544-3.