PUBLICATION

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

Authors

Roychaudhury, A., Lee, Y.R., Choi, T.I., Thomas, M.G., Kahn, T.N., Yousaf, H., Skinner, C., Maconachie, G., Crosier, M., Horak, H., Constantinescu, C.S., Kim, T.Y., Lee, K.H., Kyung, J.J., Wang, T., Ku, B., Chodirker, B.N., Hammer, M.F., Gottlob, I., Norton, W.H.J., Gorlei, R., Kim, H.G., Graziano, C., Pippucci, T., Lovino, E., Montanari, F., Severi, G., Toro, C., Boerkoel, C.F., Cha, H.S., Choi, C.Y., Kim, S., Yoon, J.Y., Gilmore, K., Vora, N.L., Davis, E.E., Chudley, A.E., Schwartz, C.E., and Kim, C.H.

ID

ZDB-PUB-240730-17

Date

2024

Source

Annals of neurology 96(5): 914-931 (Journal)

Registered Authors

Kim, Cheol-Hee, Thomas, Mervyn

Keywords

none

MeSH Terms

Male
Zebrafish*
Animals
Child, Preschool
X-Linked Intellectual Disability/genetics
Cognition/physiology
Protein Serine-Threonine Kinases*/genetics
Child
Eye
Humans
Female
Adolescent
Adult
Intellectual Disability/genetics

(all 14)

PubMed

39073169 Full text @ Ann. Neurol.

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

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
her4.1	srpk3^{ck243a/ck243a}	standard conditions	Protruding-mouth	brain neuron	ISH	Fig. 4
her4.1	srpk3^{ck243b/ck243b}	standard conditions	Protruding-mouth	brain neuron	ISH	Fig. 4
her4.1	WT	standard conditions	Protruding-mouth	brain neuron	ISH	Fig. 4
isl1a	srpk3^{ck243a/ck243a}	standard conditions	Protruding-mouth	brain motor neuron	ISH	Fig. 4
isl1a	srpk3^{ck243b/ck243b}	standard conditions	Protruding-mouth	brain motor neuron	ISH	Fig. 4
isl1a	WT	standard conditions	Protruding-mouth	brain motor neuron	ISH	Fig. 4
srpk3	srpk3^{ck243a/ck243a}	standard conditions	Protruding-mouth	brain	ISH	Fig. 4
srpk3	srpk3^{ck243a/ck243a}	standard conditions	Adult	brain	RTPCR	Fig. 4
srpk3	srpk3^{ck243b/ck243b}	standard conditions	Adult	brain	RTPCR	Fig. 4
srpk3	srpk3^{ck243b/ck243b}	standard conditions	Protruding-mouth	brain	ISH	Fig. 4

1 - 10 of 20

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
srpk3^{ck243a/ck243a}	control	Adult	social behavior decreased process quality, abnormal	Fig. 6
srpk3^{ck243a/ck243a}	standard conditions	Protruding-mouth	brain srpk3 expression decreased distribution, abnormal	Fig. 4
srpk3^{ck243a/ck243a}	standard conditions	Day 5	optokinetic behavior decreased process quality, abnormal	Fig. 5
srpk3^{ck243a/ck243a}	standard conditions	Day 5	swim bladder uninflated, abnormal	Fig. 4
srpk3^{ck243a/ck243a}	standard conditions	Adult	brain srpk3 expression decreased amount, abnormal	Fig. 4
srpk3^{ck243a/ck243a}	standard conditions	Adult	valvula cerebelli decreased size, abnormal	Fig. 7
srpk3^{ck243b/ck243b}	control	Adult	social behavior decreased process quality, abnormal	Fig. 6
srpk3^{ck243b/ck243b}	standard conditions	Protruding-mouth	brain srpk3 expression decreased distribution, abnormal	Fig. 4
srpk3^{ck243b/ck243b}	standard conditions	Day 5	optokinetic behavior decreased process quality, abnormal	Fig. 5
srpk3^{ck243b/ck243b}	standard conditions	Day 5	swim bladder uninflated, abnormal	Fig. 4

1 - 10 of 12

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ck243a		Small Deletion	srpk3
ck243b		Small Deletion	srpk3

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
syndromic X-linked intellectual disability			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
srpk3	CRISPR3-srpk3	CRISPR

Fish

Fish
srpk3^{ck243a/ck243a}
srpk3^{ck243b/ck243b}
WT

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Roychaudhury et al., 2024 ZDB-PUB-240730-17 PMID:39073169

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

Roychaudhury et al., 2024

ZDB-PUB-240730-17
PMID:39073169