PUBLICATION

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

Authors
Zhao, W., Gao, X., Qiu, S., Gao, B., Gao, S., Zhang, X., Kang, D., Han, W., Dai, P., Yuan, Y.
ID
ZDB-PUB-190702-1
Date
2019
Source
EBioMedicine   45: 408-421 (Journal)
Registered Authors
Keywords
ATP6V1B2, Cognitive defects, Dominant deafness-onychodystrophy (DDOD) syndrome, V-ATPases
MeSH Terms
  • Adult
  • Animals
  • Cochlea
  • Deafness/genetics*
  • Deafness/physiopathology
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Infant
  • Intellectual Disability/genetics*
  • Intellectual Disability/physiopathology
  • Male
  • Mice
  • Mice, Transgenic
  • Pedigree
  • Phenotype
  • Vacuolar Proton-Translocating ATPases/genetics*
  • Zebrafish/genetics
PubMed
31257146 Full text @ EBioMedicine
Abstract
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.
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.
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 Atp6v1b2Arg506X//Arg506X mice were observed.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping