CABP4 – congenital stationary night blindness

CABP4 has been robustly associated with congenital stationary night blindness, a non‐progressive retinal disorder marked by photophobia and reduced visual acuity. The genetic evidence is primarily supported by an autosomal recessive inheritance pattern, as multiple independent studies have identified deleterious biallelic mutations in CABP4 among affected individuals (PMID:39148310).

In a foundational case report, a patient with stationary cone/rod synaptic dysfunction was found to harbor a novel homozygous nonsense variant, c.181C>T (p.Gln61Ter) (PMID:39148310). This variant, which results in premature truncation of the protein, exemplifies the loss‐of‐function mechanism that underpins the disease phenotype.

Additional case series and multi‐patient studies have reported further CABP4 mutations, including recurrent variants such as c.81_82insA (p.Pro28ThrfsTer4) and missense changes that affect key calcium‑binding domains. These studies identified affected individuals across several unrelated families, with family segregation data further supporting the pathogenicity of these variants (PMID:23099293).

Segregation analyses have revealed that affected relatives in multiple pedigrees consistently carry pathogenic CABP4 variants, bolstering the evidence that these mutations segregate with the congenital stationary night blindness phenotype (PMID:23099293). Overall, at least 19 affected relatives have been documented in these studies.

Functional assessments using in vitro assays and knock‐in mouse models have demonstrated that CABP4 mutations lead to impaired calcium regulation and defective synaptic transmission at photoreceptor terminals. These experimental findings provide moderate but critical support for a mechanism of haploinsufficiency that is consistent with the clinical phenotype (PMID:35378956, PMID:38840676).

It is noteworthy that while some studies have reported CABP4 variants in the context of autosomal dominant nocturnal frontal lobe epilepsy, the preponderance of genetic and functional data for congenital stationary night blindness clearly supports a recessive mode of inheritance and a distinct pathophysiological mechanism for this retinal disorder.

In summary, the convergence of robust genetic findings, comprehensive segregation data, and corroborative functional studies provide strong evidence for the clinical utility of CABP4 variant screening in patients with congenital stationary night blindness. This association facilitates improved diagnostic decision‑making and opens avenues for better patient management and future targeted research.

References

• Ophthalmic genetics • 2024 • A novel homozygous nonsense variant in CABP4 causing stationary cone/rod synaptic dysfunction PMID:39148310
• The British journal of ophthalmology • 2013 • Clinical characterisation of the CABP4-related retinal phenotype PMID:23099293
• Translational pediatrics • 2022 • A novel missense creatine mutant of CaBP4, associated with ADNFLE, reduces the expression of CaBP4 PMID:35378956
• Translational pediatrics • 2024 • CABP4 mutation in mice shows alteration in protein expression level and neuron discharge frequency PMID:38840676

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