title: The mutational spectrum of human malignant autosomal recessive osteopetrosis.
abstract: 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.
authors.affiliation: Department of Human Genome and Multifactorial Disease, Istituto di Tecnologie, Biomediche Avanzate, Consiglio Nazionale delle Ricerche, via Fratelli Cervi 93, 20090 Segrate (MI), Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sobacchi
authors.forename: A
authors.initials: A
authors.lastname: Frattini
authors.forename: P
authors.initials: P
authors.lastname: Orchard
authors.forename: O
authors.initials: O
authors.lastname: Porras
authors.forename: I
authors.initials: I
authors.lastname: Tezcan
authors.forename: M
authors.initials: M
authors.lastname: Andolina
authors.forename: R
authors.initials: R
authors.lastname: Babul-Hirji
authors.forename: I
authors.initials: I
authors.lastname: Baric
authors.forename: N
authors.initials: N
authors.lastname: Canham
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
authors.forename: S
authors.initials: S
authors.lastname: Dupuis-Girod
authors.forename: I
authors.initials: I
authors.lastname: Ellis
authors.forename: A
authors.initials: A
authors.lastname: Etzioni
authors.forename: A
authors.initials: A
authors.lastname: Fasth
authors.forename: A
authors.initials: A
authors.lastname: Fisher
authors.forename: B
authors.initials: B
authors.lastname: Gerritsen
authors.forename: V
authors.initials: V
authors.lastname: Gulino
authors.forename: E
authors.initials: E
authors.lastname: Horwitz
authors.forename: V
authors.initials: V
authors.lastname: Klamroth
authors.forename: E
authors.initials: E
authors.lastname: Lanino
authors.forename: M
authors.initials: M
authors.lastname: Mirolo
authors.forename: A
authors.initials: A
authors.lastname: Musio
authors.forename: G
authors.initials: G
authors.lastname: Matthijs
authors.forename: S
authors.initials: S
authors.lastname: Nonomaya
authors.forename: L D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: H D
authors.initials: HD
authors.lastname: Ochs
authors.forename: A
authors.initials: A
authors.lastname: Superti Furga
authors.forename: J
authors.initials: J
authors.lastname: Valiaho
authors.forename: J L
authors.initials: JL
authors.lastname: van Hove
authors.forename: M
authors.initials: M
authors.lastname: Vihinen
authors.forename: D
authors.initials: D
authors.lastname: Vujic
authors.forename: P
authors.initials: P
authors.lastname: Vezzoni
authors.forename: A
authors.initials: A
authors.lastname: Villa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics; D002880:Chromosomes, Human, Pair 11; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010022:Osteopetrosis / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*; D014617:Vacuoles / Q000201:enzymology / Q000235:genetics
chemical_list: D018118:Chloride Channels; D025262:Vacuolar Proton-Translocating ATPases