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Stehr, A.M.* ; Lenberg, J.* ; Friedman, J.* ; Dobbelaere, D.* ; Imbard, A.* ; Lévy, J.* ; Donoghue, S.* ; Derive, N.* ; Stoeva, R.* ; Gueguen, P.* ; Zech, M.

Consolidating the role of mutated ATP2B2 in neurodevelopmental and cerebellar pathologies.

Clin. Genet., DOI: 10.1111/cge.14622 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
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Plasma membrane calcium ATPases (PMCAs) encoded by ATP2B genes have been implicated in Mendelian diseases with ataxia, dystonia, and intellectual disability. Work to date has shown that ATP2B2 (encoding PMCA2) is required for synaptic function and Purkinje-cell integrity in the cerebellum. A recent case series has linked ATP2B2 to a novel entity, characterized by neurodevelopmental and movement phenotypes, in only seven individuals. We called for collaboration to collect five unpublished families affected by the new rare ATP2B2-related condition. Exome-/genome sequencing-identified genotypes included four likely pathogenic/pathogenic heterozygous de novo missense variants and one dominantly inherited end-truncating frameshift allele. The six affected individuals shared features with the described patients including developmental delay, cognitive disturbances, epilepsy, autistic traits, and motor disorders. Striking cerebellar atrophy was observed in one affected individual. In association with hearing loss and movement abnormalities, we report a recurrent p.(Glu457Lys) substitution, previously documented in a neurologically impaired ATP2B2 mouse mutant. Our study further delineates the mutational spectrum and presentation of a human syndrome caused by ATP2B2 variants, confirming the importance of PMCA2 in neurotypical and cerebellar development.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Atp2b2 ; Cerebellar Atrophy ; Developmental Delay ; Intellectual Disability ; Movement Disorder ; Neurodevelopmental Disorder; Variants
ISSN (print) / ISBN 0009-9163
e-ISSN 1399-0004
Journal Clinical Genetics
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants EJP RD Joint Transnational Call 2022
Free State of Bavaria
Technical University of Munich - Institute for Advanced Study
German Federal Ministry of Education and Research (BMBF, Bonn, Germany)