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ATP6V1B2 – Zimmermann-Laband syndrome

ATP6V1B2 encodes the B2 subunit of the vacuolar H⁺-ATPase (V-ATPase), a multisubunit proton pump essential for lysosomal and endosomal acidification. Heterozygous missense variants in ATP6V1B2 underlie autosomal dominant Zimmermann-Laband syndrome (ZLS), characterized by gingival hypertrophy, nail aplasia or hypoplasia, hypertrichosis, coarse facial features, and variable intellectual disability.

Inheritance is autosomal dominant with de novo occurrence of pathogenic alleles. ZLS probands present in early childhood with gingival enlargement (HP:0002327), terminal phalangeal hypoplasia, generalized hypertrichosis (HP:0000998), and intellectual disability (HP:0001249).

Genetic evidence is supported by identification of a recurrent de novo missense allele, c.1454G>C (p.Arg485Pro), in two unrelated ZLS patients ([PMID:25915598]). This variant has not been observed in healthy controls and segregates with disease in both cases, indicating a high prior probability of pathogenicity.

Functional studies demonstrate that ZLS-associated ATP6V1B2 missense substitutions operate via a gain-of-function mechanism. Structural modeling predicts disrupted V-ATPase assembly, and cellular assays reveal upregulated proton transport, increased lysosomal acidification, abnormal lysosomal morphology, and impaired autophagic flux ([PMID:39210597]). Aberrant V-ATPase activity additionally perturbs cilium biogenesis, consistent with the multisystemic features of ZLS.

No conflicting evidence has been reported. The concordance of de novo genetic findings, recurrent alleles, and mechanistic cellular data establishes a robust link between ATP6V1B2 dysfunction and ZLS.

Key Take-home: Screening ATP6V1B2 for de novo gain-of-function missense variants is clinically informative for autosomal dominant Zimmermann-Laband syndrome.

References

  • Nature genetics • 2015 • Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. PMID:25915598
  • HGG advances • 2024 • Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. PMID:39210597

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Recurrent de novo variant in 2 unrelated ZLS probands ([PMID:25915598]); consistent clinical spectrum across multiple cohorts

Genetic Evidence

Moderate

De novo missense p.Arg485Pro in 2 probands; recurrent allele; limited segregation data

Functional Evidence

Moderate

Cellular assays demonstrate gain-of-function with increased V-ATPase activity, altered lysosomal acidification, and autophagy defects ([PMID:39210597])