The mutational spectrum of human malignant autosomal recessive osteopetrosis

Cristina Sobacchi, Annalisa Frattini, Paul Orchard, Oscar Porras, Ilhan Tezcan, Marino Andolina, Riyana Babul-Hirji, Ivo Baric, Natalie Canham, David Chitayat, Sophie Dupuis-Girod, Ian Ellis, Amos Etzioni, Anders Fasth, Alain Fisher, Bert Gerritsen, Virginia Gulino, Edwin Horwitz, Verena Klamroth, Edoardo LaninoMassimiliano Mirolo, Antonio Musio, Gert Matthijs, Shigeaki Nonomaya, Luigi D. Notarangelo, Hans D. Ochs, Andrea Superti Furga, Jouni Valiaho, Johan L K Van Hove, Mauno Vihinen, Dragana Vujic, Paolo Vezzoni, Anna Villa

Research output: Contribution to journalArticlepeer-review

188 Scopus citations


Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogenous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for ∼50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition.

Original languageEnglish (US)
Pages (from-to)1767-1773
Number of pages7
JournalHuman molecular genetics
Issue number17
StatePublished - Aug 15 2001


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