SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
29 Jul 2024
29 Jul 2024
Historique:
revised:
07
07
2024
received:
30
05
2023
accepted:
08
07
2024
medline:
29
7
2024
pubmed:
29
7
2024
entrez:
29
7
2024
Statut:
aheadofprint
Résumé
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. 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. 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. 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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Institute of Child Health and Development (NICHD)
ID : R01HD105868
Organisme : National Institute of Mental Health (NIMH)
ID : R01MH106826
Organisme : NINDS NIH HHS
ID : R01NS073854
Pays : United States
Organisme : Natural Sciences and Engineering Research Council of Canada
ID : 311637
Organisme : The South Carolina Department of Disabilities and Special Needs
ID : 2015-45
Organisme : Ministry of Oceans and Fisheries
ID : 20220027
Organisme : National Institute for Health Research
ID : CL-2017-11-003
Organisme : National Research Foundation of Korea
ID : 2020R1A5A8017671
Organisme : National Research Foundation of Korea
ID : RS-2024-00349650
Organisme : Ministero Italiano della Salute, Programma di Ricerca Finalizzata 2018
ID : RF-2018- 12366314
Informations de copyright
© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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