The mutational spectrum of human malignant autosomal recessive osteopetrosis

• Published in: Human molecular genetics Vol. 10; no. 17; pp. 1767 - 1773
• Main Authors: SOBACCHI, Cristina, FRATTINI, Annalisa, DUPUIS-GIROD, Sophie, ELLIS, Ian, ETZIONI, Amos, FASTH, Anders, FISHER, Alain, GERRITSEN, Bert, GULINO, Virginia, HORWITZ, Edwin, KLAMROTH, Verena, LANINO, Edoardo, ORCHARD, Paul, MIROLO, Massimiliano, MUSIO, Antonio, MATTHIJS, Gert, NONOMAYA, Shigeaki, NOTARANGELO, Luigi D, OCHS, Hans D, SUPERTI FURGA, Andrea, VALIAHO, Jouni, VAN HOVE, Johan L. K, VIHINEN, Mauno, PORRAS, Oscar, VUJIC, Dragana, VEZZONI, Paolo, VILLA, Anna, TEZCAN, Ilhan, ANDOLINA, Marino, BABUL-HIRJI, Riyana, BARIC, Ivo, CANHAM, Natalie, CHITAYAT, David
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.08.2001
• Subjects: Amino Acid Sequence; Animals; ATP6i gene; Base Sequence; Biological and medical sciences; Cell Line; Chloride Channels - genetics; Chromosomes, Human, Pair 11; DNA Mutational Analysis; Exons; Female; Fundamental and applied biological sciences. Psychology; Genes, Recessive; Haplotypes; Humans; Infant; Infant, Newborn; Introns; Male; Molecular and cellular biology; Molecular Sequence Data; Mutation; Osteopetrosis - enzymology; Osteopetrosis - genetics; Polymerase Chain Reaction; Sequence Homology, Amino Acid; TCIRG1 gene; Vacuolar Proton-Translocating ATPases - genetics; Vacuoles - enzymology; Vacuoles - genetics
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/10.17.1767

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogeneous 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 approximately 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.