Bone mineral density and laboratory evaluation of a type II autosomal dominant osteopetrosis carrier

Takács, István; Cooper, Heather; Weaver, David D.; Econs, Michael J.

doi:10.1002/(sici)1096-8628(19990702)85:1<9::aid-ajmg4>3.0.co;2-3

Cited by 8 publications

(6 citation statements)

References 10 publications

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“…We also found that the reduction in the acidification level in osteoclasts from different patients was of differing severity (data not shown), which could potentially explain the nonhomogenous penetrance of the ADOII phenotype. 27,28,34 These data correlate very well with the data from the ClC-7 knockout mice, demonstrating an almost absent acidification in the osteoclasts. 6 Furthermore, we measured the area of removed calcium phosphate on the Osteologic coverslips, and we found that the area, as well as the number of resorption events was reduced in the ADOII cells, thereby supporting our evidence that the acidification is defective in these osteoclasts.…”

Section: Discussionsupporting

confidence: 83%

Characterization of Osteoclasts from Patients Harboring a G215R Mutation in ClC-7 Causing Autosomal Dominant Osteopetrosis Type II

Henriksen

Gram

Schaller

et al. 2004

The American Journal of Pathology

114

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Autosomal dominant osteopetrosis II (ADOII) is a relatively benign disorder caused by a missense mutation in the ClCN7 gene. In this study, we characterize the osteoclasts from patients with ADOII, caused by a G215R mutation, and investigate the effect on osteoclast function in vitro. Osteoclasts from ADOII patients and healthy age-and sex-matched controls, were used to evaluate osteoclastogenesis, cell fusion, acidification, and resorptive activity. ADOII osteoclasts in vivo have increased number and size. However, in vitro we observed no significant changes in the osteoclast formation rate, the morphology, and the expression of markers, such as cathepsin K and tartrate-resistant acid phosphatase. When mature ADOII osteoclasts were investigated on mineralized bone, they degraded the bone material, however only to 10 to 20% of the level in controls. We show by acridine orange, that the reduced chloride transport leads to reduced acidification. We show that the residual activity is sensitive to inhibitors of cathepsins and chloride channels, confirming that resorption is reduced but present. In conclusion, this is the first functional in vitro study of human ADOII osteoclasts. We show normal osteoclastogenesis in ADOII osteoclasts. However, the residual activity of the ClC-7 channel in ADOII osteoclasts does not allow sufficient acidification and thereby resorption. The osteoclasts ability to dissolve the inorganic phase of bone is essential for the degradation of the organic bone matrix, and thereby for the maintenance of the skeleton. The inorganic phase of bone consists of hydroxyapatite crystals, and the dissolution of this matrix requires a decrease in pH, which is facilitated by active transport of protons into the resorption lacunae.

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Section: Discussionsupporting

confidence: 83%

Characterization of Osteoclasts from Patients Harboring a G215R Mutation in ClC-7 Causing Autosomal Dominant Osteopetrosis Type II

Henriksen

Gram

Schaller

et al. 2004

The American Journal of Pathology

114

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“…Given the family history of an affected maternal aunt, which we were not able to confirm, we hypothesized that this family had an autosomal dominant disorder, although only one affected person was available for study. Of note, families EOP1, EOP2, and EOP3 have previously been reported (4,8,11) …”

Section: Methodsmentioning

confidence: 88%

“…Interestingly, these obligate gene carriers also have a normal biochemical evaluation and cannot be identified by phenotype alone. (3,8) The positional candidate approach (9) has been used successfully to identify the gene responsible for ADO2. Initially, the ADO2 gene locus was reported in one Danish family to be linked to genetic markers on chromosome 1p21, (10) but subsequent studies demonstrated that the vast majority of kindreds with ADO2 were not linked to this region.…”

Section: Introductionmentioning

confidence: 99%

Chloride Channel 7 (ClCN7) Gene Mutations and Autosomal Dominant Osteopetrosis, Type II

Waguespack

Koller

White

et al. 2003

Journal of Bone and Mineral Research

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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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“…In addition, the mean serum level of tartrate-resistant acid phosphatase was normal (1.2±2 U per liter), and serum levels of the brain isoform of creatine kinase were undetectable; these two biochemical markers may be elevated in patients with osteopetrosis. 24,25 The mean level of urinary N-telopeptide of type 1 collagen, a marker of bone resorption, was normal in the affected subjects (Table 2). Circulating levels of the receptor for activation of nuclear factork B ligand and osteoprotegerin, cytokines that regulate rates of bone resorption, 26 were also normal.…”

Section: Biochemical Findingsmentioning

confidence: 97%

High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5

et al. 2002

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Bone mineral density and laboratory evaluation of a type II autosomal dominant osteopetrosis carrier

Cited by 8 publications

References 10 publications

Characterization of Osteoclasts from Patients Harboring a G215R Mutation in ClC-7 Causing Autosomal Dominant Osteopetrosis Type II

Characterization of Osteoclasts from Patients Harboring a G215R Mutation in ClC-7 Causing Autosomal Dominant Osteopetrosis Type II

Chloride Channel 7 (ClCN7) Gene Mutations and Autosomal Dominant Osteopetrosis, Type II

High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5

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