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

Item Type:	Article
Title:	Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis
Creators Name:	Kornak, U. and Schulz, A. and Friedrich, W. and Uhlhaas, S. and Kremens, B. and Voit, T. and Hasan, C. and Bode, U. and Jentsch, T.J. and Kubisch, C.
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.
Keywords:	Amino Acid Sequence, Base Sequence, Human Chromosomes Pair 11, DNA Mutational Analysis, Exons, Haplotypes, Introns, Microsatellite Repeats, Molecular Sequence Data, Osteopetrosis, Pedigree, Proton-Translocating ATPases, Reverse Transcriptase Polymerase Chain Reaction, Sequence Deletion, Vacuoles
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	9
Number:	13
Page Range:	2059-2063
Date:	12 August 2000
Official Publication:	http://hmg.oxfordjournals.org/cgi/content/abstract/9/13/2059
PubMed:	View item in PubMed

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