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The mutational spectrum of human malignant autosomal recessive osteopetrosis

Sobacchi, C; Frattini, A; Orchard, P; Porras, O; Tezcan, I; Andolina, M; Babul-Hirji, R; Baric, I; Canham, N and Chitayat, D, et al. (2001) In Human Molecular Genetics 10(17). p.1767-1773
Abstract
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 similar to 50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions,... (More)
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 similar to 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. (Less)
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Human Molecular Genetics
volume
10
issue
17
pages
1767 - 1773
publisher
Oxford University Press
external identifiers
  • wos:000171125600006
  • scopus:0035880417
ISSN
0964-6906
DOI
10.1093/hmg/10.17.1767
language
English
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no
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d2c0390c-e60b-48c4-9c0f-16431424898a (old id 3851573)
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2013-06-28 15:24:36
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2018-04-08 03:37:50
@article{d2c0390c-e60b-48c4-9c0f-16431424898a,
  abstract     = {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 similar to 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.},
  author       = {Sobacchi, C and Frattini, A and Orchard, P and Porras, O and Tezcan, I and Andolina, M and Babul-Hirji, R and Baric, I and Canham, N and Chitayat, D and Dupuis-Girod, S and Ellis, I and Etzioni, A and Fasth, A and Fisher, A and Gerritsen, B and Gulino, V and Horwitz, E and Klamroth, V and Lanino, E and Mirolo, M and Musio, A and Matthijs, G and Nonomaya, S and Notarangelo, LD and Ochs, HD and Furga, AS and Valiaho, J and van Hove, JLK and Vihinen, Mauno and Vujic, D and Vezzoni, P and Villa, A},
  issn         = {0964-6906},
  language     = {eng},
  number       = {17},
  pages        = {1767--1773},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {The mutational spectrum of human malignant autosomal recessive osteopetrosis},
  url          = {http://dx.doi.org/10.1093/hmg/10.17.1767},
  volume       = {10},
  year         = {2001},
}