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.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.

Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schönberg disease (Chloride Channel 7 Deficiency Osteopetrosis) among the sclerosing bone disorders

“…Patient 7 succumbed to what seems to have been a unique form of OPT, and patient 8 had an ''intermediate'' type of OPT (see below). CLCN7 mutation analysis performed elsewhere (14,15) was positive for each of the 4 A-SD probands tested (patients 2, 3, 5, and 14).…”

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

“…This is not unexpected taking into account the high intra-familiar clinical variability ranging from asymptomatic to severely affected. This also implies a reduced disease penetrance, which has been estimated to be between 66 and 94% (3,19,20,57,58). A clear explanation for the reduced penetrance and the intra-familial variability is not available.…”

Diseases Affecting Bone Quality: Beyond Osteoporosis

“…Therefore, the bone remodeling process is shifted toward bone resorption, resulting in an imbalance of bone turnover that causes fragility fracture. Conversely, in a setting where there is a defect in osteoclast function, such as in osteopetrosis, this could lead to a lack of bone heterogeneity, microdamage accumulation, and ultimately fragility fracture [18,105].…”

“…When there is defective resorption, as is the case with osteopetrosis, the osteoclasts fail to remove bone, resulting in a marked increase in bone density, microdamage accumulation, loss of bone heterogeneity, and abnormalities of osseous structure (Fig. 4) [18,71,105]. Despite the presence of increased bone density on imaging studies, the bones of these patients are fragile and fractures are common.…”