Chloride channel 7 (CLCN7) gene mutations and autosomal dominant osteopetrosis, type II

Steven G. Waguespack, Daniel L. Koller, Kenneth White, Tonya Fishburn, Gwenaelle Carn, Kenneth Buckwalter, Michelle Johnson, Maureen Kocisko, Wayne E. Evans, Tatiana Foroud, Michael Econs

Research output: Contribution to journalArticle

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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. Introduction: 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 ClCN7 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 ClCN7 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.

Original languageEnglish
Pages (from-to)1513-1518
Number of pages6
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume18
Issue number8
DOIs
StatePublished - Aug 2003

Fingerprint

Osteopetrosis
Chloride Channels
Mutation
Genes
Penetrance
Missense Mutation
Bone and Bones
Genetic Heterogeneity
Restriction Fragment Length Polymorphisms
Genetic Recombination

Keywords

  • Autosomal dominant osteopetrosis
  • Chloride channel 7
  • Mutations
  • Type II

ASJC Scopus subject areas

  • Surgery

Cite this

Chloride channel 7 (CLCN7) gene mutations and autosomal dominant osteopetrosis, type II. / Waguespack, Steven G.; Koller, Daniel L.; White, Kenneth; Fishburn, Tonya; Carn, Gwenaelle; Buckwalter, Kenneth; Johnson, Michelle; Kocisko, Maureen; Evans, Wayne E.; Foroud, Tatiana; Econs, Michael.

In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Vol. 18, No. 8, 08.2003, p. 1513-1518.

Research output: Contribution to journalArticle

Waguespack, Steven G. ; Koller, Daniel L. ; White, Kenneth ; Fishburn, Tonya ; Carn, Gwenaelle ; Buckwalter, Kenneth ; Johnson, Michelle ; Kocisko, Maureen ; Evans, Wayne E. ; Foroud, Tatiana ; Econs, Michael. / Chloride channel 7 (CLCN7) gene mutations and autosomal dominant osteopetrosis, type II. In: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2003 ; Vol. 18, No. 8. pp. 1513-1518.
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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. Introduction: 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 ClCN7 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 ClCN7 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.",
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AU - Koller, Daniel L.

AU - White, Kenneth

AU - Fishburn, Tonya

AU - Carn, Gwenaelle

AU - Buckwalter, Kenneth

AU - Johnson, Michelle

AU - Kocisko, Maureen

AU - Evans, Wayne E.

AU - Foroud, Tatiana

AU - Econs, Michael

PY - 2003/8

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N2 - 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. Introduction: 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 ClCN7 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 ClCN7 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.

AB - 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. Introduction: 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 ClCN7 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 ClCN7 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.

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