SRPK3 and X-linked Intellectual Disability

SRPK3 has emerged as a critical gene implicated in X-linked intellectual disability. Two independent studies have reported missense variations in SRPK3 in patients presenting with cognitive deficits, abnormal eye movements, and motor ataxia. The first study identified three missense mutations in seven patients from three independent families, while the second study reported four missense variants and one truncating variant in nine patients from five unrelated families (PMID:36993381, PMID:39073169). These findings underscore a robust genetic signal linking SRPK3 to the disorder.

In the first study, detailed phenotyping revealed intellectual disability accompanied by agenesis of the corpus callosum and abnormal smooth pursuit eye movements. The clinical presentation was consistently observed across families, and the identified variants were all missense changes confirming a deleterious effect in a gene critical for neurodevelopment. The recurrent detection of these variants bolsters the argument for a causative role for SRPK3 (PMID:36993381).

The second study further expanded the mutational landscape of SRPK3 by identifying additional missense variants, including a recurrent mutation, and a putative truncating variant. Affected individuals shared overlapping features such as intellectual disability, cerebellar agenesis, and abnormal ocular motility. This independent replication, along with clear familial segregation in multiple unrelated families, strengthens the genetic evidence for this association (PMID:39073169).

Genetic evidence is further supported by the identification of the variant c.475C>G (p.His159Asp), which is present in the published abstracts and variant lists. This variant, together with others identified across studies, suggests a consistent mutational spectrum in SRPK3 that correlates with the XLID phenotype. The recurrence of c.475C>G (p.His159Asp) highlights its potential as a molecular marker for diagnostic screening (PMID:36993381, PMID:39073169).

Functional assessment studies included the use of zebrafish knockout models, which recapitulated salient features of the human phenotype. These models displayed significant deficits in spontaneous eye movement and exhibited both cerebellar agenesis and behavioral impairments mimicking those seen in patients. Such robust experimental results provide compelling evidence that loss of SRPK3 function contributes to the neurodevelopmental pathology observed in X-linked intellectual disability (PMID:36993381, PMID:39073169).

No significant conflicting evidence has been reported, and both clinical and experimental data convergently support the role of SRPK3 in this disease context. The combined genetic and functional evidence outlines a clear pathomechanism, with disrupted mRNA processing and synaptic function likely underlying the clinical features.

In summary, the convergence of genetic findings, robust segregation data, and consistent functional evidence from zebrafish models firmly establish SRPK3 as a compelling candidate for X-linked intellectual disability. This integrated evidence not only aids in diagnostic decision‑making but also informs future research and potential therapeutic development.

References

• Research Square • 2023 • Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X‑linked intellectual disability PMID:36993381
• Annals of Neurology • 2024 • SRPK3 Is Essential for Cognitive and Ocular Development in Humans and Zebrafish, Explaining X‑Linked Intellectual Disability PMID:39073169

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