Disease relevance of ATP6V0A4

• Previously we have shown that mutations in two kidney-specific genes, ATP6V1B1 and ATP6V0A4, encoding the H(+)-ATPase B1 and a4 subunit isoforms, cause recessive distal renal tubular acidosis (dRTA) [1].
• ATP6V1B mutations have been associated with early sensorineural hearing loss (SNHL), whereas ATP6V0A4 mutations are classically associated with either late-onset SNHL or normal hearing [2].
• However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood [3].
• Among 38 samples of non-Hodgkin lymphoma, 1 anaplastic large cell lymphoma expressed genes MAGE-A1, -A2, -A3, -A4, and -A12, and 1 lymphoepithelioid T-cell lymphoma expressed gene MAGE-A4 [4].
• Alzheimer A4 peptide, gamma-trace, leukoencephalopathy, and hereditary cerebral hemorrhage with amyloidosis-Dutch type [5].

Psychiatry related information on ATP6V0A4

• A quantitative study of the coincidence of blood vessels and A4 protein deposits in Alzheimer's disease [6].
• These data indicate that severe diffuse beta A4 deposits in the neocortex do not induce dementia [7].

High impact information on ATP6V0A4

• The importance in final urinary acidification along the collecting system is highlighted by monogenic defects in two subunits (ATP6V0A4, ATP6V1B1) of the vacuolar H(+)-ATPase in patients with distal renal tubular acidosis [8].
• Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing [9].
• Immunofluorescence studies in human kidney cortex revealed that ATP6N1B localizes almost exclusively to the apical surface of -intercalated cells [9].
• We previously localized a gene for dRTA with preserved hearing to 7q33-34 (ref. 4). We report here the identification of this gene, ATP6N1B, which encodes an 840 amino acid novel kidney-specific isoform of ATP6N1A, the 116-kD non-catalytic accessory subunit of the proton pump [9].
• One hundred fifty-four unrelated French Caucasian subjects were typed for 11 RFLPs at or near the APOA1-C3-A4 gene cluster on the long arm of chromosome 11 [10].

Chemical compound and disease context of ATP6V0A4

• Human data raised the possibility that coronary heart disease is associated with mutations in the apolipoprotein gene cluster APOA1/C3/A4 that result in multideficiency of cluster-encoded apolipoproteins and hypoalphalipoproteinemia [11].

Biological context of ATP6V0A4

• These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time [3].
• Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity [3].
• That a4 W520L affects both Vo and V1 subunits is a unique phenotype for any V-ATPase subunit mutation and supports the concerted pathway for V-ATPase assembly in vivo [12].
• We have isolated and sequenced genomic clones of the human Fc gamma RIII-A and Fc gamma RIII-B genes, located their transcription initiation sites, identified a different organization of their 5' regions, and demonstrated four distinct classes of Fc gamma RIII-A transcripts (a1-a4) compared with a single class of Fc gamma RIII-Bb1 transcripts [13].
• These studies establish the importance of the VPH1 gene and vesicular acidification in the virulence of C. neoformans [14].

Anatomical context of ATP6V0A4

• We show here that ATP6V0A4 is expressed within the human inner ear [3].
• Immunoblots confirmed wild type levels for V-ATPase a, A, and B subunits on vacuolar membranes. a4 G812R resulted in defective growth on selective media with V-ATPase hydrolytic and pumping activity decreased by 83-85% yet with wild type levels of a, A, and B subunits on vacuolar membranes [12].
• This protein shares high sequence homology to the yeast vacuolar H(+)-ATPase subunit, Vph1p, and the 116 kDa proton pump of the rat and bovine synaptic vesicle, Vpp1 [15].
• The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR-2 [16].
• The same changes in the inward-rectifier K+ channel were also observed in a4 2 blastomeres which were induced by cell contact with an A4-1 blastomere [17].

Associations of ATP6V0A4 with chemical compounds

• To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well-established roles in influencing plasma HDL-cholesterol and triglyceride concentrations [18].
• Insertional mutagenesis and plasmid rescue were used to identify the VPH1 gene by screening for mutants defective in laccase activity [14].
• A novel intragenetic PvuII marker in the human neuronal nicotinic acetylcholine receptor a4 subunit gene (CHRNA4). Mutation and polymorphism report no. 62. Online [19].
• Moreover, expression of the paralogous group 4 genes (HOX A4, HOX B4, HOX C4, and HOX D4), together with that of isolated genes in the network, appears to discriminate between white and brown adipose tissue [20].
• Inactivating mutations introduced at the A4/A3 elements, binding sites for the glucose-regulated homeodomain transcription factor PDX-1, did not diminish the response to Ex-4, although a marked reduction of basal promoter activity was observed [21].

Other interactions of ATP6V0A4

• Therefore, STV1 and VPH1 have distinct functions in FBPase degradation [22].

Analytical, diagnostic and therapeutic context of ATP6V0A4

• Northern-blot analysis demonstrated ATP6N1B expression in kidney but not other main organs [9].
• Specificity of a4 binding to this peptide was confirmed by enzyme-linked immunosorbent assay [23].
• The structure of the bark lectin RPbAI (isoform A4) from Robinia pseudoacacia has been determined by protein crystallography both in the free form and complexed with N-acetylgalactosamine [24].
• No amyloid angiopathy was seen with Congo red stain although beta A 4 deposits were seen in vessel walls with immunocytochemistry [7].
• Elective balloon angioplasty reduced the delta STV1 during exercise in only three of six patients (50%) with right ventricular infarction [25].

References