ATP6V1A – Developmental and epileptic encephalopathy 93

Developmental and epileptic encephalopathy 93 (DEE93) is a recently defined autosomal dominant neurological disorder caused by heterozygous mutations in the ATP6V1A gene. Clinically, patients present with global developmental delay, hypotonia, intellectual disability and early-onset refractory seizures (PMID:40225911). Early genetic diagnosis informs differential diagnosis, treatment planning and genetic counseling.

To date, 31 unrelated individuals harboring de novo missense ATP6V1A variants have been reported worldwide (PMID:40225911), including two novel mutations (c.746C>T (p.Pro249Leu), c.1061G>T (p.Trp354Leu)) identified in two new patients (PMID:40225911). Additionally, four de novo variants (p.Pro27Arg, p.Asp100Tyr, p.Asp349Asn, p.Asp371Gly) were described in four patients with overlapping encephalopathy and epilepsy phenotypes (PMID:29668857). Most pathogenic alleles are missense substitutions clustering within key functional domains of the V1 A subunit.

Representative pathogenic variants include c.746C>T (p.Pro249Leu) (NM_001690.4) (PMID:40225911), which disrupts V-ATPase function by altering subunit stability and proton transport. No recurrent or founder variants have been identified, and segregation beyond de novo occurrence is minimal (no familial segregation reported).

Functional investigations in cellular and neuronal models demonstrate variant-specific mechanisms: the p.Asp100Tyr mutation leads to protein degradation and reduced lysosomal markers consistent with loss-of-function, whereas p.Asp349Asn enhances proton pumping indicative of gain-of-function; both impair neurite elongation and synaptic connectivity (PMID:29668857). Yeast site-directed mutagenesis of conserved residues in the glycine-rich loop further confirms their critical role in V-ATPase assembly and activity (PMID:9115229; PMID:12569096).

Regulatory studies reveal that αB-crystallin and mTORC1 complex with ATP6V1A to stabilize the protein and regulate lysosomal pH, with loss of this interaction leading to accelerated degradation and pH dysregulation (PMID:31786107). These data illustrate a spectrum of pathogenic mechanisms—haploinsufficiency, dominant-negative or gain-of-function—converging on disrupted proton pump activity and neuronal dysfunction.

No conflicting evidence has refuted the gene–disease link. Additional reports in epilepsy cohorts suggest variant-specific phenotypic variability, including cases without epilepsy but with developmental delay, expanding the clinical spectrum.

Key take-home: Autosomal dominant ATP6V1A mutations cause DEE93 through disruption of lysosomal acidification and proton transport, and should be considered in early-onset epilepsy with developmental impairment where functional assays may guide precision therapy.

References

• Human mutation • 2024 • Clinical and Genetic Characteristics of Two Cases With Developmental and Epileptic Encephalopathy 93 Caused by Novel ATP6V1A Mutations and Literature Review. PMID:40225911
• Brain • 2018 • De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy. PMID:29668857
• The Journal of biological chemistry • 1997 • Site-directed mutagenesis of the yeast V-ATPase A subunit. PMID:9115229
• The Journal of biological chemistry • 2003 • Mutational analysis of the non-homologous region of subunit A of the yeast V-ATPase. PMID:12569096
• Biochimica et biophysica acta. General subjects • 2020 • Heat shock factor 4 regulates lysosome activity by modulating the αB-crystallin-ATP6V1A-mTOR complex in ocular lens. PMID:31786107

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