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De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

ABSTRACT: Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

SUBMITTER: Kury S 

PROVIDER: S-EPMC5673671 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

Küry Sébastien S   van Woerden Geeske M GM   Besnard Thomas T   Proietti Onori Martina M   Latypova Xénia X   Towne Meghan C MC   Cho Megan T MT   Prescott Trine E TE   Ploeg Melissa A MA   Sanders Stephan S   Stessman Holly A F HAF   Pujol Aurora A   Distel Ben B   Robak Laurie A LA   Bernstein Jonathan A JA   Denommé-Pichon Anne-Sophie AS   Lesca Gaëtan G   Sellars Elizabeth A EA   Berg Jonathan J   Carré Wilfrid W   Busk Øyvind Løvold ØL   van Bon Bregje W M BWM   Waugh Jeff L JL   Deardorff Matthew M   Hoganson George E GE   Bosanko Katherine B KB   Johnson Diana S DS   Dabir Tabib T   Holla Øystein Lunde ØL   Sarkar Ajoy A   Tveten Kristian K   de Bellescize Julitta J   Braathen Geir J GJ   Terhal Paulien A PA   Grange Dorothy K DK   van Haeringen Arie A   Lam Christina C   Mirzaa Ghayda G   Burton Jennifer J   Bhoj Elizabeth J EJ   Douglas Jessica J   Santani Avni B AB   Nesbitt Addie I AI   Helbig Katherine L KL   Andrews Marisa V MV   Begtrup Amber A   Tang Sha S   van Gassen Koen L I KLI   Juusola Jane J   Foss Kimberly K   Enns Gregory M GM   Moog Ute U   Hinderhofer Katrin K   Paramasivam Nagarajan N   Lincoln Sharyn S   Kusako Brandon H BH   Lindenbaum Pierre P   Charpentier Eric E   Nowak Catherine B CB   Cherot Elouan E   Simonet Thomas T   Ruivenkamp Claudia A L CAL   Hahn Sihoun S   Brownstein Catherine A CA   Xia Fan F   Schmitt Sébastien S   Deb Wallid W   Bonneau Dominique D   Nizon Mathilde M   Quinquis Delphine D   Chelly Jamel J   Rudolf Gabrielle G   Sanlaville Damien D   Parent Philippe P   Gilbert-Dussardier Brigitte B   Toutain Annick A   Sutton Vernon R VR   Thies Jenny J   Peart-Vissers Lisenka E L M LELM   Boisseau Pierre P   Vincent Marie M   Grabrucker Andreas M AM   Dubourg Christèle C   Tan Wen-Hann WH   Verbeek Nienke E NE   Granzow Martin M   Santen Gijs W E GWE   Shendure Jay J   Isidor Bertrand B   Pasquier Laurent L   Redon Richard R   Yang Yaping Y   State Matthew W MW   Kleefstra Tjitske T   Cogné Benjamin B   Petrovski Slavé S   Retterer Kyle K   Eichler Evan E EE   Rosenfeld Jill A JA   Agrawal Pankaj B PB   Bézieau Stéphane S   Odent Sylvie S   Elgersma Ype Y   Mercier Sandra S  

American journal of human genetics 20171101 5

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 f  ...[more]

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