Roychaudhury, A. orcid.org/0000-0003-1497-4909, Lee, Y., Choi, T. et al. (36 more authors) (2024) SRPK3 Is essential for cognitive and ocular development in humans and zebrafish, explaining X-linked intellectual disability. Annals of Neurology, 96 (5). pp. 914-931. ISSN 0364-5134
Abstract
Objective
Intellectual disability is often the outcome of neurodevelopmental disorders and is characterized by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) is a subset of these disorders caused by genetic defects on the X chromosome, affecting about 2 out of 1,000 males. In syndromic form, it leads to a broad range of cognitive, behavioral, ocular, and physical disabilities.
Methods
Employing exome or genome sequencing, here we identified 4 missense variants (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K, c.953C > T; p.S318L) and a putative truncating variant (c.1413_1414del; p.Y471*) in the SRPK3 gene in 9 XLID patients from 5 unrelated families. To validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish.
Results
The 8 patients ascertained postnatally shared common clinical features including intellectual disability, agenesis of the corpus callosum, abnormal eye movement, and ataxia. A ninth case, ascertained prenatally, had a complex structural brain phenotype. Together, these data indicate a pathological role of SRPK3 in neurodevelopmental disorders. In post-fertilization day 5 larvae (free swimming stage), KO zebrafish exhibited severe deficits in eye movement and swim bladder inflation, mimicking uncontrolled ocular movement and physical clumsiness observed in human patients. In adult KO zebrafish, cerebellar agenesis and behavioral abnormalities were observed, recapitulating human phenotypes of cerebellar atrophy and intellectual disability.
Interpretation
Overall, these results suggest a crucial role of SRPK3 in the pathogenesis of syndromic X-linked intellectual disability and provide new insights into brain development, cognitive and ocular dysfunction in both humans and zebrafish. ANN NEUROL 2024
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
Keywords: | Biomedical and Clinical Sciences; Neurosciences; Clinical Sciences; Mental Health; Neurosciences; Behavioral and Social Science; Genetics; Intellectual and Developmental Disabilities (IDD); Congenital Structural Anomalies; Brain Disorders; Rare Diseases; Eye Disease and Disorders of Vision; Basic Behavioral and Social Science; Pediatric; Biological and endogenous factors; Neurological; Quality Education |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 07 Aug 2024 14:21 |
Last Modified: | 20 Nov 2024 16:38 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1002/ana.27037 |
Related URLs: | |
Sustainable Development Goals: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:215695 |