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

Abstract

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.

Effects of Pyridoxine Deficiency on Hippocampal Function and Its Possible Association with V-Type Proton ATPase Subunit B2 and Heat Shock Cognate Protein 70

“…ATP6V1B2 is ubiquitously expressed in the brain [50] and is related to synaptic transmission [51]. Atp6v1b2 knock-in mice show cognitive defects in passive avoidance and novel object recognition tests [52] and the ATP6V1B2 rs1106634 A allele is a risk factor in hippocampal cognitive deficits [53]. HSC70 is upregulated in Alzheimer's disease brains [54].…”

The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

“…Using a zebrafish model replicating this mutation, it was shown that the V-ATPase can still assemble but that the affinity of some subunits comprising the holoenzyme is lowered. A role of the B2 subunit in other types of cognitive impairment has also been recognized ( 188 , 189 ).…”

Molecular Mechanisms and Biological Functions of Autophagy for Genetics of Hearing Impairment

“…In particular, dominant deafness-onychodystrophy (DDOD) syndrome caused by de novo mutation c.1516 C > N (p.Arg506X) in ATP6V1B2 is a rare disorder with chief complaints of severe deafness, onychodystrophy, and brachydactyly (Table 1) [38]. This group's latest research [39] indicated four interesting results: (1) atp6v1b2 knockdown zebrafish had developmental defects in multiple organs and systems; (2) Atp6v1b2 c.1516 C > N knock-in mice led to cognitive disorders, based on the impaired hippocampal CA1 region from the pathology;…”

“…In particular, dominant deafness-onychodystrophy (DDOD) syndrome caused by de novo mutation c.1516 C > N (p.Arg506X) in ATP6V1B2 is a rare disorder with chief complaints of severe deafness, onychodystrophy, and brachydactyly ( Table 1 ) [ 38 ]. This group’s latest research [ 39 ] indicated four interesting results: (1) atp6v1b2 knockdown zebrafish had developmental defects in multiple organs and systems; (2) Atp6v1b2 c.1516 C > N knock-in mice led to cognitive disorders, based on the impaired hippocampal CA1 region from the pathology; (3) the normal hearing thresholds of Atp6v1b2 c.1516 C > N in 24-week-old knock-in mice, suggested that a compensation mechanism exists in the auditory system; and (4) V-ATPases assembly still occurred in Atp6v1b2 c.1516 C > N. However, the interaction between the E and B2 subunits was weaker than in the wild type (WT). They confirmed that the defectiveness of Atp6v1b2 leads to CNS impairments and extends the phenotype range of DDOD syndrome.…”