Polymorphisms of the <i>CLCN7</i> Gene Are Associated With BMD in Women

Pettersson, Ulrika; Mirolo, Max; Taranta, Anna; Frattini, Annalisa; McGuigan, Fiona; Vezzoni, Paolo; Teti, Anna; Hul, Wim Van; Reid, David M.; Villa, Anna; Ralston, Stuart H.

doi:10.1359/jbmr.050717

Cited by 31 publications

(24 citation statements)

References 27 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mechanism by which this repeat influences the function of ClC-7 is unclear, but an effect on exon-intron splicing cannot be excluded. The V418M and the VNTR polymorphism are to some degree in linkage disequilibrium (62). Therefore, the real causal variant remains to be demonstrated.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

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

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

show abstract

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

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

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Classical association studies typically involve choosing a candidate gene that is known to have effects on bone metabolism on the basis of knowledge about skeletal physiology or bone biology. Genes that are mutated in rare monogenic bone diseases have also proved to be a rich source of polymorphisms that regulate BMD in the normal population (Grant et al 1996;Ferrari et al 2004;Sobacchi et al 2004;Pettersson et al 2005). Association studies are relatively easy to perform and can be powered to detect small effects, but spurious results are often reported due to confounding factors, small sample size, and population stratification (Ioannidis 2003).…”

Section: Association Studiesmentioning

confidence: 99%

“…Homozygous inactivation mutations in CLCN7 cause a severe form of recessive osteopetrosis (Kornak et al 2001), whereas heterozygous missense mutations of CLCN7 cause autosomal dominant osteopetrosis (Balemans et al 2005). Prompted by this observation, Pettersson et al (2005) looked for evidence of an association between polymorphisms of CLCN7 and BMD in normal individuals and found that a common polymorphism in exon 15 of CLCN7 that results in a methionine-to-valine amino acid change was associated with BMD in normal women. Further studies will be required to determine if this polymorphism is functionally important and to replicate the observation in other populations.…”

Section: Clcn7mentioning

confidence: 99%

Genetic regulation of bone mass and susceptibility to osteoporosis

Ralston¹,

Crombrugghe²

2006

Genes Dev.

289

226

View full text Add to dashboard Cite

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risksuch as ultrasound properties of bone, skeletal geometry, and bone turnover-is high, although heritability of fracture is modest. Many different genetic variants of modest effect size are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Linkage studies in rare Mendelian bone diseases have identified several previously unknown genes that play key roles in regulating bone mass and bone turnover. In many instances, subtle polymorphisms in these genes have also been found to regulate BMD in the general population. Although there has been extensive progress in identifying the genetic variants that regulate susceptibility to osteoporosis, most of the genes and genetic variants that regulate bone mass and susceptibility to osteoporosis remain to be discovered.Osteoporosis is characterized by reduced bone mass, alterations in the microarchitecture of bone tissue, reduced bone strength, and an increased risk of fracture (Kanis et al. 1994). Osteoporosis is a common condition that affects up to 30% of women and 12% of men at some point in life. The prevalence of osteoporosis increases with age due to an imbalance in the rate at which bone is removed and replaced during the bone remodeling cycle, which is an important physiological process that is essential for maintenance of a healthy skeleton. Many factors influence the risk of osteoporosis-including diet, physical activity, medication use, and coexisting diseases-but one of the most important clinical risk factors is a positive family history, emphasizing the importance of genetics in the pathogenesis of osteoporosis. In this article, we first review the evidence for a genetic contribution to osteoporosis and related phenotypes, and discuss the mechanisms by which mutations and polymorphisms in genes that regulate susceptibility to osteoporosis affect major signaling pathways in bone. Genetic influences on osteoporosisGenetic factors have long been recognized as playing an important role in the pathogenesis of osteoporosis. Evidence from twin and family studies suggests that between 50% and 85% of the variance in peak bone mass is genetically determined, depending on skeletal site and the age of the subjects studied (Smith et al. 1973;Pocock et al. 1987;Krall and Dawson-Hughes 1993;Gueguen et al. 1995). Heritability studies have also shown evidence of significant genetic effects on other key determinants of osteoporotic fracture risk, including quantitative ultrasound properties of bone (Arden et al. 1996), femoral neck geometry (Arden et al. 1996), muscle strength (Arden and Spector 1997), bone turnover markers (Hunter et al. 2001), and body mass index (Kaprio et al. 1995). The role of genetic factors in the pathogenesis of bon...

show abstract

“…The gene is made up by 25 exons and is highly polymorphic (69), but it is unclear whether specific polymorphisms could be associated with its incomplete penetrance (69)(70)(71). Environmental modifiers, genetic modifiers as well as epigenetic regulation could represent other mechanisms favoring the incomplete penetrance, but further work is necessary to discover those specifically modulating the expression of the dominant negative CLCN7 gene mutants.…”

Section: Autosomal Dominant Osteopetrosesmentioning

confidence: 99%

Osteopetroses, emphasizing potential approaches to treatment

Teti

Econs

2017

Bone

Self Cite

View full text Add to dashboard Cite

Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone fragility. Osteoclasts are bone resorbing cells that contribute to bone growth and renewal through the erosion of the mineralized matrix. Alongside the bone forming activity by osteoblasts, osteoclasts allow the skeleton to grow harmonically and maintain a healthy balance between bone resorption and formation. Osteoclast impairment in osteopetroses prevents bone renewal and deteriorates bone quality, causing atraumatic fractures. Osteopetroses vary in severity and are caused by mutations in a variety of genes involved in bone resorption or in osteoclastogenesis. Frequent signs and symptoms include osteosclerosis, deformity, dwarfism and narrowing of the bony canals, including the nerve foramina, leading to hematological and neural failures. The disease is autosomal, with only one extremely rare form associated so far to the X-chromosome, and can have either recessive or dominant inheritance. Recessive ostepetroses are generally lethal in infancy or childhood, with a few milder forms clinically denominated intermediate osteopetroses. Dominant osteopetrosis is so far associated only with mutations in the CLCN7 gene and, although described as a benign form, it can be severely debilitating, although not at the same level as recessive forms, and can rarely result in reduced life expectancy. Severe osteopetroses due to osteoclast autonomous defects can be treated by Hematopoietic Stem Cell Transplant (HSCT), but those due to deficiency of the pro-osteoclastogenic cytokine, RANKL, are not suitable for this procedure.Likewise, it is unclear as to whether HSCT, which has high intrinsic risks, results in clinical improvement in autosomal dominant osteopetrosis. Therefore, there is an unmet medical need to identify new therapies and studies are currently in progress to test gene and cell therapies, small interfering RNA approach and novel pharmacologic treatments.

show abstract

Polymorphisms of the CLCN7 Gene Are Associated With BMD in Women

Cited by 31 publications

References 27 publications

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

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

Genetic regulation of bone mass and susceptibility to osteoporosis

Osteopetroses, emphasizing potential approaches to treatment

Contact Info

Product

Resources

About