ATP6V1B2 – Neurodevelopmental Disorder

ATP6V1B2 encodes the B2 subunit of the vacuolar H⁺-ATPase, a proton pump essential for organelle acidification and neurotransmitter loading. Loss or alteration of ATP6V1B2 function has been implicated in a spectrum of neurodevelopmental disorders characterized by developmental delay, intellectual disability and epilepsy. Recent large-scale sequencing efforts and individual case studies have refined this gene–disease relationship and informed diagnostic screening.

Genetic evidence stems from Exome Pool-Seq screening of 96 unrelated NDD cases, which identified rare ATP6V1B2 variants among 27 candidates in established NDD genes ([PMID:29158550]). Follow-up in-depth analyses uncovered at least four de novo variants in unrelated probands: c.973G>C (p.Gly325Arg) in a patient with Lennox–Gastaut syndrome ([PMID:37633739]), c.1120G>T (p.Glu374Gly) in epilepsy with ID ([PMID:36135319]), c.1165del (p.Tyr389IlefsTer13) in a child with epilepsy and NMD‐evasion ([PMID:39075926]), and recurrent truncating p.Arg506* observed in individuals with ID and seizures ([PMID:37628590]). These variants comprise both missense and loss-of-function classes and occur in the heterozygous state with de novo inheritance.

The inheritance pattern is autosomal dominant with incomplete penetrance and variable expressivity. No extended pedigrees are reported; all cases are simplex with de novo events (affected_relatives 0). The variant spectrum includes missense changes at conserved residues (p.Gly325Arg, p.Glu374Gly) and protein-truncating alleles (p.Tyr389IlefsTer13, p.Arg506*).

Functional studies corroborate pathogenicity. Heterozygous Atp6v1b2emR506* mice exhibit locomotor hyperactivity, reduced anxiety behaviors, interictal epileptiform activity and lowered seizure threshold to pentylenetetrazol, mirroring patient phenotypes ([PMID:37628590]). In Drosophila, knockdown of the ATP6V1B2 ortholog Vha55 induces seizure-like behaviors and climbing defects, supporting a loss-of-function mechanism ([PMID:39075926]). CRISPR/Cas9 correction of c.1516C>T in patient-derived iPSCs restores normal pluripotency and differentiation potential, confirming variant specificity ([PMID:33714068]).

Collectively, multiple de novo ATP6V1B2 variants in unrelated patients, consistent autosomal dominant inheritance, and concordant cross-species models fulfill criteria for a ClinGen Moderate gene–disease association. Functional assays demonstrate haploinsufficiency as the likely pathogenic mechanism.

Key Take-home: Heterozygous ATP6V1B2 variants should be considered in diagnostic panels for neurodevelopmental disorders with epilepsy, as they support a clinically actionable autosomal dominant mechanism.

References

• European journal of human genetics : EJHG • 2017 • Exome Pool-Seq in neurodevelopmental disorders. PMID:29158550
• Brain & development • 2023 • ATP6V1B2-related disorders featuring Lennox-Gastaut-syndrome: A case-based overview. PMID:37633739
• American journal of medical genetics. Part A • 2022 • A novel pathogenic ATP6V1B2 variant: Widening the genotypic spectrum of the epileptic neurodevelopmental phenotype. PMID:36135319
• Clinical genetics • 2024 • Epilepsy due to potential loss of ATP6V1B2 function with mechanistic insight by a Drosophila Vha55 model. PMID:39075926
• Genes • 2023 • The ATP6V1B2 DDOD/DOORS-Associated p.Arg506 Variant Causes Hyperactivity and Seizures in Mice.* PMID:37628590
• Stem cell research • 2021 • Generation of a gene corrected human isogenic iPSC line (CPGHi002-A-1) from a DDOD patient with heterozygous c.1516 C>T mutation in the ATP6V1B2 gene. PMID:33714068

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