Human Molecular Genetics, 2001, Vol. 10, No. 17 1767-1773
© 2001 Oxford University Press
The mutational spectrum of human malignant autosomal recessive osteopetrosis
Department of Human Genome and Multifactorial Disease, Istituto di Tecnologie, Biomediche Avanzate, Consiglio Nazionale delle Ricerche, via Fratelli Cervi 93, 20090 Segrate (MI), Italy, 1Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA, 2Department of Immunology, National Children’s Hospital, San José, Costa Rica, 3Hacettepe University Children’s Hospital, Ankara, Turkey, 4Istituto per l’Infanzia, Trieste, Italy, 5Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada, 6Department of Pediatrics, University Hospital Center, Zagreb, Croatia, 7Clinical Genetic Unit, Birmingham Women’s Hospital, Edgbaston, Birmingham, UK, 8The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada, 9Unité d’Immunologie et d’Hématologie Pédiatriques, Hopital Necker-Enfant Malades, Paris, France, 10Alder Hey Children’s Hospital, Liverpool, UK, 11Division of Pediatrics, Rambam Medical Centre, Haifa, Israel, 12Department of Pediatrics, University of Göteborg, The Queen Silvia Children’s Hospital, 41685 Göteborg, Sweden, 13Department of Pediatrics, Medical Center Rijnmond-Zuid, Olympiaweg 350, 3078 HT, Rotterdam, The Netherlands, 14Istituto di Medicina Molecolare ‘Angelo Nocivelli’, Clinica Pediatrica, Universita’ di Brescia, Italy, 15St Jude Children’s Research Hospital, Memphis, TN, USA, 16 Institut für Humangenetik, Westfaelische Wilhelms-Universitaet, Muenster, Germany, 17Department of Pediatric Hematology and Oncology, BMT Unit, IRCCS G. Gaslini, Genova, Italy, 18Center for Human Genetics, University of Leuven, Leuven, Belgium, 19Department of Pediatrics, School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan, 20University of Washington School of Medicine, Division of Immunology, Infectious Diseases and Rheumatology, Department of Pediatrics, Box 356320, University of Washington School of Medicine, Seattle, WA 98195-6320, USA, 21Division of Metabolism and Molecular Pediatrics, University Children’s Hospital, CH-8032 Zurich, Switzerland, 22Institute of Medical Technology, FIN-33014 University of Tampere, Finland and Tampere University Hospital, FIN-33520 Tampere, Finland, 23Department of Pediatrics, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium and 24Bone Marrow Transplant Unit, Mother and Child Health Institute, Belgrade, Yugoslavia
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.
+ To whom correspondence should be addressed. Tel: +39 02 26422636; Fax: +39 02 26422660; Email: villa@itba.mi.cnr.it
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