SRPK3 – X-Linked Intellectual Disability

Intellectual disability (ID) encompasses a spectrum of neurodevelopmental disorders marked by significant impairments in intellectual and adaptive functioning. X-linked intellectual disability (XLID) affects approximately 1.7 per 1,000 males and results from pathogenic variants in genes on the X chromosome. Recent exome sequencing in affected families has implicated SRPK3 as a novel XLID gene, with downstream functional validation in zebrafish models.

In a cohort of seven affected males from three independent XLID pedigrees, three hemizygous missense variants in SRPK3 were identified: c.475C>G (p.His159Asp), c.1373C>A (p.Thr458Asn), and c.1585G>A (p.Glu529Lys) (PMID:36993381). All variants segregated with ID and additional features including agenesis of the corpus callosum and ataxia. No loss-of-function or structural variants were reported, and no recurrent or founder alleles have been described to date.

Phenotypically, affected males presented with global intellectual disability (HP:0001249), agenesis of the corpus callosum (HP:0001274), ataxia (HP:0001251), and abnormal smooth pursuit eye movement. Carrier females were asymptomatic or showed mild learning difficulties, consistent with X-linked recessive inheritance.

Functional assessment in a zebrafish knockout (KO) model of the SRPK3 ortholog revealed significant defects in spontaneous and smooth pursuit eye movements at day 5 of larval development, impaired swim bladder inflation, and adult cerebellar agenesis with social interaction deficits. These findings mirror key clinical features observed in patients and support a loss-of-function mechanism for SRPK3 in neurodevelopment (PMID:36993381).

Mechanistically, SRPK3 encodes a serine/arginine-rich protein kinase involved in mRNA processing and synaptic vesicle regulation. Disruption of SRPK3 likely impairs neuronal RNA splicing and synaptic transmission, leading to the observed cognitive and motor phenotypes.

No conflicting evidence has been reported. Together, genetic segregation across multiple families and concordant zebrafish KO data provide strong support for SRPK3 in XLID. Additional cohorts and rescue studies would further solidify this association.

Key Take-Home: SRPK3 hemizygous missense variants cause an X-linked intellectual disability characterized by corpus callosum agenesis and ocular motor deficits, with functional zebrafish KO confirmation supporting clinical diagnostic utility.

References

• Research square • 2023 • Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X-linked intellectual disability. PMID:36993381

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