to both dominant and recessive osteopetrosis. Approximately 50% of patients with recessive infantile malignant osteopetrosis have mutations to the a3 subunit isoform of V-ATPase. In humans, 26 mutations have been identified in V-ATPase subunit isoform a3, found in osteoclasts, that result in the bone disease autosomal recessive osteopetrosis. Distal renal tubular acidosis (dRTA) The importance of V-ATPase activity in renal proton secretion is highlighted by the inherited disease distal renal tubular acidosis. In all cases, renal tubular acidosis results from a failure of the normal renal mechanisms that regulate systemic pH. There are four types of renal tubular acidosis. Type 1 is distal renal tubular acidosis and results from a failure of the cortical collecting duct to acidify the urine below pH 5. Some patients with autosomal recessive dRTA also have sensorineural hearing loss. Inheritance of this type of RTA results from either mutations to V-ATPase subunit isoform B1 or isoform a4 or mutations of band 3 (also called AE1), a Cl-/HCO3- exchanger. Twelve different mutations to V-ATPase isoform B1 and twenty-four different mutations in a4 lead to dRTA. Reverse transcription polymerase chain reaction studies have shown expression of the a4 subunit in the intercalated cell of the kidney and in the cochlea. dRTA caused by mutations in the a4 subunit gene in some cases can be associated with deafness due to a failure to normally acidify the endolymph of the inner ear. X-linked myopathy with excessive autophagy (XMEA) X-linked myopathy with excessive autophagy is a rare genetic disease resulting from mutations in the VMA21 gene. The disease has a childhood onset and results in a slowly progressive muscle weakness, typically beginning in the legs, and some patients can eventually require wheelchair assistance with advanced age. The Vma21 protein assists in assembly of the V-ATPase, and XMEA associated mutations result in decreased activity of the V-ATPase and increased lysosomal pH. Nomenclature The term Vo has a lowercase letter "o" (not the number "zero") in subscript. The "o" stands for oligomycin, which binds to the homologous region in F-ATPase. It is worth noting that the human gene notations at NCBI designate it as "zero" rather than the letter "o". For example, the gene for the human c subunit of Vo is listed in NCBI gene database as "ATP6V0C" (with a zero), rather than "ATP6VOC" (with an "o"). Many pieces of literature make this mistake as well. See also ATP synthase F-ATPase