The mutational spectrum of human malignant autosomal recessive osteopetrosis

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogenous autosomal recessive disorder of bone metabolism, which, if un treated, has a fatal outcome. Our group, as well as others, have recently i dentified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/oste oclast interface, are responsible for a subset of this condition. By sequen cing the ATP6i gene in arOP patients from 44 unrelated families with a worl dwide distribution we have now established that ATP6i mutations are respons ible for similar to 50% of patients affected by this disease. The vast majo rity of these mutations (40 out of 42 alleles, including seven deletions, t wo 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 u nrelated arOP patients from Costa Rica, where this disease is apparently mu ch 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 p erform prenatal diagnosis: both fetuses were predicted not to be affected a nd two healthy babies were born. This study contributes to the determinatio n of genetic heterogeneity of arOP and allows further delineation of the ot her genetic defects causing this severe condition.