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Lookup NU author(s): Moira Crosier
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 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.
Author(s): Roychaudhury A, Lee Y-R, Choi T-I, Thomas MG, Khan TN, Yousaf H, Skinner C, Maconachie G, Crosier M, Horak H, Constantinescu CS, Kim T-Y, Lee K-H, Kyung J-J, Wang T, Ku B, Chodirker BN, Hammer MF, Gottlob I, Norton WHJ, Gerlai R, Kim H-G, Graziano C, Pippucci T, Iovino E, Montanari F, Severi G, Toro C, Boerkoel CF, Cha HS, Choi CY, Kim S, Yoon J-H, Gilmore K, Vora NL, Davis EE, Chudley AE, Schwartz CE, Kim C-H
Publication type: Article
Publication status: Published
Journal: Annals of Neurology
Year: 2024
Pages: ePub ahead of Print
Online publication date: 29/07/2024
Acceptance date: 08/07/2024
Date deposited: 16/08/2024
ISSN (print): 0364-5134
ISSN (electronic): 1531-8249
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1002/ana.27037
DOI: 10.1002/ana.27037
Data Access Statement: Data supporting the findings of this study are available upon request from the corresponding authors.
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