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Human Molecular Genetics, 2000, Vol. 9, No. 13 2059-2063
© 2000 Oxford University Press

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

Uwe Kornak, Ansgar Schulz1, Wilhelm Friedrich1, Siegfried Uhlhaas2, Bernhard Kremens3, Thomas Voit3, Carola Hasan4, Udo Bode4, Thomas J. Jentsch+ and Christian Kubisch2

Zentrum für Molekulare Neurobiologie Hamburg, Martinistrasse 85, ZMNH, Universität Hamburg, D-20246 Hamburg, Germany, 1Universitätskinderklinik, Universität Ulm, D-89075 Ulm, Germany, 2Institut für Humangenetik, Universität Bonn, D-53111 Bonn, Germany, 3Klinik und Poliklinik für Kinder- und Jugendmedizin, Universität-Gesamthochschule Essen, D-45122 Essen, Germany and 4Zentrum für Kinderheilkunde, Universität Bonn, D-53113 Bonn, Germany

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.

+ To whom correspondence should be addressed. Tel: +49 40 42803 4741; Fax: +49 40 42803 4839; Email: jentsch@plexus.uke.uni-hamburg.de


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