TY - JOUR
T1 - SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X-Linked Intellectual Disability
AU - Roychaudhury, Arkaprava
AU - Lee, Yu Ri
AU - Choi, Tae Ik
AU - Thomas, Mervyn G.
AU - Khan, Tahir N.
AU - Yousaf, Hammad
AU - Skinner, Cindy
AU - Maconachie, Gail
AU - Crosier, Moira
AU - Horak, Holli
AU - Constantinescu, Cris S.
AU - Kim, Tae Yoon
AU - Lee, Kang Han
AU - Kyung, Jae Jun
AU - Wang, Tao
AU - Ku, Bonsu
AU - Chodirker, Bernard N.
AU - Hammer, Michael F.
AU - Gottlob, Irene
AU - Norton, William H.J.
AU - Gerlai, Robert
AU - Kim, Hyung Goo
AU - Graziano, Claudio
AU - Pippucci, Tommaso
AU - Iovino, Emanuela
AU - Montanari, Francesca
AU - Severi, Giulia
AU - Toro, Camilo
AU - Boerkoel, Cornelius F.
AU - Cha, Hyo Sun
AU - Choi, Cheol Yong
AU - Kim, Sungjin
AU - Yoon, Je Hyun
AU - Gilmore, Kelly
AU - Vora, Neeta L.
AU - Davis, Erica E.
AU - Chudley, Albert E.
AU - Schwartz, Charles E.
AU - Kim, Cheol Hee
N1 - Publisher Copyright:
© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2024/11
Y1 - 2024/11
N2 - 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.
AB - 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.
KW - Agenesis
KW - Expression
KW - Eye-movements
KW - Gene
KW - Spliceosome
UR - http://www.scopus.com/inward/record.url?scp=85200023539&partnerID=8YFLogxK
U2 - 10.1002/ana.27037
DO - 10.1002/ana.27037
M3 - Article
AN - SCOPUS:85200023539
SN - 0364-5134
VL - 96
SP - 914
EP - 931
JO - Annals of Neurology
JF - Annals of Neurology
IS - 5
ER -