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PreprintCited by 3Genetics and Neurodevelopmental DisordersGenomics and Rare DiseasesDown syndrome and intellectual disability research

Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X‐linked intellectual disability

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Kim, Cheol-Hee, Lee, Yu-Ri, Thomas, Mervyn, Roychaudhury, Arkaprava, Skinner, Cindy, Maconachie, Gail, Crosier, Moira, Horak, Holli +11 more·2023·Research Square
DOI 10.21203/rs.3.rs-2683050/v1PMC PMC10055661
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Abstract

Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired intellectual and adaptive functioning. X-linked ID (XLID) disorders, caused by defects in genes on the X chromosome, affect 1.7 out of 1,000 males. Employing exome sequencing, we identified three missense mutations (c.475C > G; p.H159D, c.1373C > A; p.T458N, and c.1585G > A; p.E529K) in the SRPK3 gene in seven XLID patients from three independent families. Clinical features common to the patients are intellectual disability, agenesis of the corpus callosum, abnormal smooth pursuit eye movement, and ataxia. SRPK proteins are known to be involved in mRNA processing and, recently, synaptic vesicle and neurotransmitter release. In order to validate SRPK3 as a novel XLID gene, we established a knockout (KO) model of the SRPK3 orthologue in zebrafish. In day 5 of larval stage, KO zebrafish showed significant defects in spontaneous eye movement and swim bladder inflation. In adult KO zebrafish, we found agenesis of cerebellar structures and impairments in social interaction. These results suggest an important role of SRPK3 in eye movements, which might reflect learning problems, intellectual disability, and other psychiatric disorders.

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Authors
Kim, C.-H., Lee, Y.-R., Thomas, M., Roychaudhury, A., Skinner, C., Maconachie, G., Crosier, M., Horak, H., Constantinescu, C., Choi, T.-I., Kyung, J.-J., Wang, T., Ku, B., Chodirker, B., Hammer, M., Gottlob, I., Norton, W., Chudley, A., & Schwartz, C.
Affiliations
  • Chungnam National University (KR)
  • University of Leicester (GB)
  • Greenwood Genetic Center (US)
  • Newcastle University (GB)
  • University of Arizona (US)
  • University of Nottingham (GB)
  • Johns Hopkins University (US)
  • Korea Research Institute of Bioscience and Biotechnology (KR)
  • University of Manitoba (CA)
Corresponding author
  • Kim, Cheol-Hee
  • Schwartz, Charles
ORCID
Venue
Research Square
Publisher
Springer Science and Business Media LLC
Published
2023-03-20
DOI
10.21203/rs.3.rs-2683050/v1
PMC
PMC10055661
OpenAlex
W4327915227
Cited by
3
References
4
Citations by year
2024: 3
Type
posted content
Language
en
Open access
Licence
Locations
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Institute for Health and Care Research (CL‐2017‐11‐003)
  • Ulverscroft Foundation
  • National Research Foundation (2018M3A9B8021980, 2020R1A5A8017671)
  • Ministry of Oceans and Fisheries (20220027)
  • National Research Foundation of Korea (20220027, 2020R1A5A8017671, 2021R1A2C1008506, 2018M3A9B8021980)
  • National Institute of Neurological Disorders and Stroke (R01NS073854)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
X-linked intellectual disability, smooth pursuit eye movements, agenesis of the corpus callosum, ataxia, missense mutations, cerebellar agenesis, social interaction deficits, mRNA processing, neurodevelopmental disorders

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