SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability

Arkaprava Roychaudhury, Yu Ri Lee, Tae Ik Choi, Mervyn G. Thomas, Tahir N. Khan, Hammad Yousaf, Cindy Skinner, Gail Maconachie, Moira Crosier, Holli Horak, Cris S. Constantinescu, Tae Yoon Kim, Kang Han Lee, Jae Jun Kyung, Tao Wang, Bonsu Ku, Bernard N. Chodirker, Michael F. Hammer, Irene Gottlob, William H.J. NortonRobert Gerlai, Hyung Goo Kim, Claudio Graziano, Tommaso Pippucci, Emanuela Iovino, Francesca Montanari, Giulia Severi, Camilo Toro, Cornelius F. Boerkoel, Hyo Sun Cha, Cheol Yong Choi, Sungjin Kim, Je Hyun Yoon, Kelly Gilmore, Neeta L. Vora, Erica E. Davis, Albert E. Chudley, Charles E. Schwartz*, Cheol Hee Kim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)914-931
Number of pages18
JournalAnnals of Neurology
Volume96
Issue number5
Early online dateJul 2024
DOIs
Publication statusPublished - Nov 2024
Externally publishedYes

Keywords

  • Agenesis
  • Expression
  • Eye-movements
  • Gene
  • Spliceosome

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