2000/08/12 by Uwe Kornak · 350 citations
Biochemistry, Genetics and Molecular Biology · Nursing · #ATP Synthase and ATPases Research #Bone Metabolism and Diseases #Trace Elements in Health #Osteopetrosis #Biology #Genetics #Mutation #Gene #Loss function #Locus (genetics) #Mutant #Protein subunit #Osteoclast #Molecular biology #Phenotype #Immunology
paper · pdf · doi:10.1093/hmg/9.13.2059
published in Human Molecular Genetics 9(13), 2059-2063 (Oxford University Press)
openalex publication_date 2000/08/12 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Although the gene defects for several mouse mutants with severe osteopetrosis are known, the genes underlying human infantile malignant recessive osteopetrosis remain elusive. Osteopetrosis is thought to be caused by a defect in osteoclast function. These cells degrade bone material in a tightly sealed extracellular compartment that is acidified by a vacuolar (V)-type H(+)-ATPase. Genes encoding components of the acidification machinery are candidate genes for osteopetrosis. In five of ten patients with infantile malignant osteopetrosis, we now demonstrate five different mutations in OC116, the gene encoding the a3 subunit of the V-ATPase from osteoclasts. Two independent patients were homozygous for mutations that predict a total loss of function by severely truncating the protein. By affecting a splice site, another homozygous mutation deletes 14 amino acids within the N-terminus, which interacts with other subunits of the proton pump. On the other hand, in four patients no mutations were found, and one patient from a consanguineous family did not show homozygosity at the OC116 locus, suggesting that mutations in at least one different gene may underlie osteopetrosis. Our work shows that mutations in the gene encoding the a3 subunit of the proton pump are a rather common cause of infantile osteopetrosis and suggests that this disease is genetically heterogeneous.