A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability

Background: Dominant deafness-onychodystrophy (DDOD) syndrome is a rare disorder mainly characterized by severe deafness, onychodystrophy and brachydactyly. We previously identified c.1516C > T (p.Arg506X) in ATP6V1B2 as cause of DDOD syndrome, accounting for all cases of this genetic disorder. Clinical follow-up of DDOD syndrome patients with cochlear implantation revealed the language rehabilitation was unsatisfactory although the implanted cochlea worked well, which indicates there might be learning and memory problems in DDOD syndrome patients. However, the underlying mechanisms were unknown.

Methods: atp6v1b2 knockdown zebrafish and Atp6v1b2 c.1516C > T knockin mice were constructed to explore the phenotypes and related mechanism. In mutant mice, auditory brainstem response test and cochlear morphology analysis were performed to evaluate the auditory function. Behavioral tests were used to investigate various behavioral and cognitive domains. Resting-state functional magnetic resonance imaging was used to evaluate functional connectivity in the mouse brain. Immunofluorescence, Western blot, and co-immunoprecipitation were performed to examine the expression and interactions between the subunits of V-ATPases.

Findings: atp6v1b2 knockdown zebrafish showed developmental defects in multiple organs and systems. However, Atp6v1b2 c.1516C > T knockin mice displayed obvious cognitive defects but normal hearing and cochlear morphology. Impaired hippocampal CA1 region and weaker interaction between the V1E and B2 subunits in Atp6v1b2^{Arg506X//Arg506X} mice were observed.

Interpretation: Our study extends the phenotypic range of DDOD syndrome. The impaired hippocampal CA1 region may be the pathological basis of the behavioral defects in mutant mice. The molecular mechanism underlying V-ATPases dysfunction involves a weak interaction between subunits, although the assembly of V-ATPases can still take place.