ATP2A3 – benign essential blepharospasm

ATP2A3 encodes the SERCA3 protein, a critical calcium pump involved in intracellular Ca²⁺ regulation. Benign essential blepharospasm is characterized by involuntary, bilateral orbicularis oculi spasms, and recent genetic investigations have implicated ATP2A3 as a potential contributor to this focal dystonia (PMID:29770609). The clinical presentation, marked by bilateral symptoms (HP:0012832), has spurred further studies to delineate the genetic underpinnings of the disorder.

Comprehensive whole-exome sequencing studies performed on cohorts of blepharospasm patients revealed cosegregating deleterious variants across multiple independent pedigrees. Specifically, ATP2A3 was identified with the variant c.1966C>T (p.Arg656Cys), which was observed in four independent multigenerational families (PMID:29770609). This recurrent observation across independent families supports a robust gene‑disease relationship, underscoring its relevance in the diagnostic evaluation of blepharospasm.

The genetic evidence indicates an autosomal dominant pattern of inheritance for ATP2A3 variants in the context of blepharospasm. Segregation analysis within these families has shown that affected individuals consistently carry the deleterious allele, bolstering the assertion that the c.1966C>T (p.Arg656Cys) mutation is pathogenic. Such segregation, in conjunction with the identification of the variant in multiple probands, elevates the confidence in the gene‑disease association.

Functional studies of ATP2A3, although primarily conducted in cardiac and other non‐neuronal tissues, highlight its essential role in calcium homeostasis. While direct functional assays in neural tissues or blepharospasm-specific models are lacking, the established role of SERCA3 in modulating Ca²⁺ signaling suggests that its dysfunction may contribute to the abnormal neuronal excitability underlying the dystonic movements seen in blepharospasm. This experimental data, albeit indirect, provides a plausible mechanistic link between disrupted Ca²⁺ regulation and the clinical presentation.

It is important to acknowledge that multiple candidate genes have been implicated in the genetic architecture of benign essential blepharospasm. However, the consistent cosegregation of ATP2A3 variants across several independent pedigrees distinguishes it from other potential candidates. Although functional evidence remains limited in the context of blepharospasm specifically, the alignment of genetic data with the known biological role of SERCA3 strengthens the overall gene‑disease assertion.

In summary, the combined genetic evidence—including robust segregation data and the recurrence of the c.1966C>T (p.Arg656Cys) variant in multiple families—supports a strong association between ATP2A3 and benign essential blepharospasm. Despite the current gap in direct functional studies within neuronal models, the indirect experimental findings hint at a pathogenic mechanism involving impaired Ca²⁺ regulation. Key take‑home message: Incorporating ATP2A3 genetic testing may enhance diagnostic accuracy and guide clinical decision‑making for patients with benign essential blepharospasm.

References

• Molecular genetics & genomic medicine • 2018 • Whole‐exome sequencing for variant discovery in blepharospasm PMID:29770609
• Molecular and cellular biochemistry • 1996 • Analysis of mRNA expression and cloning of a novel plasma membrane Ca(2+)-ATPase splice variant in human heart PMID:8700162

Evidence Based Scoring (AI generated)