title: Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II.
abstract: ADO2 is an uncommon sclerosing bone disorder with incomplete penetrance and variable expressivity. Positional candidate studies were performed to identify the gene responsible for ADO2. In 11 of 12 kindreds, five different missense mutations were identified in the ClCN7 gene, indicating the genetic basis and possible dominant negative mechanism for ADO2.
  
  
  BACKGROUND
  Autosomal dominant osteopetrosis, type II (ADO2) is an uncommon sclerosing bone disorder with a distinct radiographic appearance and unique clinical characteristics. We present the results from our genetic studies designed to identify the ADO2 gene through a positional candidate approach.
  
  
  METHODS
  Having identified 12 families with ADO2, we initially performed linkage studies in our seven largest kindreds and observed a summed maximum LOD score of 15.91 at marker D16S521 on chromosome 16p13.3. Critical meiotic recombination events further narrowed the putative gene region to a 7.6-cM area, which contains the candidate genes ATP6L and chloride channel 7 (ClCN7). We screened affected individuals from each ADO2 family for mutations in these genes using direct sequencing. Identified mutations were subsequently confirmed through direct sequencing or restriction fragment length polymorphism analysis. We then calculated the overall disease penetrance rate after all available at-risk family members were assessed for ClCN7 gene mutations.
  
  
  RESULTS
  No ATP6L mutations were identified in affected subjects. Subsequently, as CICN7 gene mutations were being reported, we identified two novel (L213F, R762L) and three known (G215R, R286W, R767W) missense mutations in 11 kindreds. In our large sample, disease penetrance was 66% (62 clinically affected individuals/94 subjects with the gene mutation). To date, nine different mutations have been discovered in the ClCN7 gene in 22 of 23 ADO2 families studied.
  
  
  CONCLUSIONS
  We conclude that mutations in the CICN7 gene are responsible for ADO2 and that genetic heterogeneity is unlikely to exist in this disorder. Based on the preponderance of missense mutations and the knowledge that chloride channels probably function as dimers, it seems that heterozygous ClCN7 gene mutations may cause ADO2 through a dominant negative mechanism.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Waguespack
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Koller
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
authors.forename: Tonya
authors.initials: T
authors.lastname: Fishburn
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Carn
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Buckwalter
authors.forename: Michelle
authors.initials: M
authors.lastname: Johnson
authors.forename: Maureen
authors.initials: M
authors.lastname: Kocisko
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Evans
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
mesh_terms: D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010022:Osteopetrosis / Q000235:genetics*; D019683:Penetrance
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels