Mutations in the a3 subunit of the vacuolar H⁺-ATPase cause infantile malignant osteopetrosis

Authors: Kornak, Uwe; Schulz, Ansgar¹; Friedrich, Wilhelm¹; Uhlhaas, Siegfried²; Kremens, Bernhard³; Voit, Thomas³; Hasan, Carola⁴; Bode, Udo⁴; Jentsch, Thomas J.; Kubisch, Christian²

Source: Human Molecular Genetics, Volume 9, Number 13, 12 August 2000 , pp. 2059-2063(5)

Publisher: Oxford University Press

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Abstract:

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.

Document Type: Research article

Affiliations: 1: Universitätskinderklinik, Universität Ulm, D-89075 Ulm, Germany, 2: Institut für Humangenetik, Universität Bonn, D-53111 Bonn, Germany, 3: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universität-Gesamthochschule Essen, D-45122 Essen, Germany and 4: Zentrum für Kinderheilkunde, Universität Bonn, D-53113 Bonn, Germany

Publication date: 2000-08-12

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Mutations in the a3 subunit of the vacuolar H⁺-ATPase cause infantile malignant osteopetrosis

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Mutations in the a3 subunit of the vacuolar H⁺-ATPase cause infantile malignant osteopetrosis