ATP6V1B2

ATP6V1B2 Full Name

ATPase, H+ transporting, lysosomal V1 subunit B2

ATP6V1B2 Introduction

ATP6V1B2 encodes the B2 isoform of the catalytic subunit within the peripheral V1 domain of the vacuolar-type H+-ATPase (V-ATPase) complex. The V-ATPase is a fundamental, highly conserved multi-subunit molecular motor responsible for acidifying a variety of intracellular organelles, most notably lysosomes, endosomes, and secretory vesicles. Within this massive complex, the V1 domain is responsible for the hydrolysis of ATP. Specifically, ATP6V1B2 is a non-redundant catalytic core component that couples the energy released from ATP hydrolysis to the physical rotation of the central stalk, which in turn drives the V0 membrane domain to pump protons (H+) across the membrane against their concentration gradient. This continuous proton pumping establishes the highly acidic luminal microenvironment required for lysosomal degradation, autophagic flux, and the activation of nutrient-sensing pathways such as mTORC1 on the lysosomal surface. Because of its critical role in maintaining metabolic and synaptic homeostasis, ATP6V1B2 is robustly expressed throughout the central nervous system, inner ear, and developing skeletal tissues.

Figure 1. v-ATPase assembly/disassembly. (Source: Falace A, et al. 2024)

Clinically, heterozygous dominant mutations in the ATP6V1B2 gene are the established genetic cause of a severe phenotypic spectrum of rare multisystem developmental disorders. This disease continuum primarily includes DOORS syndrome (Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation, and Seizures), Zimmermann-Laband syndrome 2 (ZLS2), and Dominant Deafness-Onychodystrophy (DDOD) syndrome. Despite the varying severities among these syndromes, they share core clinical hallmarks driven by lysosomal dysfunction during embryonic development: profound sensorineural hearing loss, hypoplasia or aplasia of the nails and terminal phalanges, significant facial dysmorphism (such as gingival enlargement in ZLS), and severe neurological impairments ranging from intellectual disability to early-onset epileptic encephalopathies. The mutant ATP6V1B2 proteins typically impair V-ATPase assembly or catalytic efficiency, leading to defective lysosomal acidification. This failure disrupts endolysosomal trafficking and protein degradation in highly vulnerable post-mitotic neurons and sensory cells, ultimately triggering neurodevelopmental arrest and the dramatic clinical manifestations seen in DOORS and ZLS patients.

Alternate Names for ATP6V1B2

ATP6V1B2; ATPase, H+ transporting, lysosomal V1 subunit B2; V-type proton ATPase subunit B, brain isoform; lysosomal 56/58kDa; V-ATPase subunit B 2; vacuolar proton pump subunit B 2; endomembrane proton pump 58 kDa subunit; ATPase, H+ transporting, V1 subunit B, isoform 2; ATPase, H+ transporting, lysosomal 56/58kD, V1 subunit B, isoform 2; ATPase, H+ transporting, lysosomal (vacuolar proton pump), beta 56/58 kDa, isoform 2

• 1. Falace A, et al. V-ATPase Dysfunction in the Brain: Genetic Insights and Therapeutic Opportunities. Cells. 2024 Aug 28;13(17):1441.
  2. Carpentieri G, et al. Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. HGG Adv. 2024 Oct 10;5(4):100349.