Loss of the ClC-7 Chloride Channel Leads to Osteopetrosis in Mice and Man

Kornak, Uwe; Kasper, Dagmar; Bösl, Michael R.; Kaiser, E.; Schweizer, Michaela; Schulz, Ansgar; Friedrich, Wilhelm; Delling, G.; Jentsch, Thomas J.

doi:10.1016/s0092-8674(01)00206-9

Cited by 906 publications

(1,061 citation statements)

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“…This form is frequently lethal in early life, despite haematological reconstitution by haematopoietic stem cell transplantation (HSCT). Few reports describe this subgroup of ARO patients, since in addition to the cases reported by our group (8 patients in Frattini et al, 2003 and1 in Shin et al, 2004), only 6 cases have been published (Cleiren et al, 2001;Kornak et al, 2001;Lam et al, 2007 ;Besbas et al, 2009). CLCN7-associated IAO is an elusive entity; it is generally classified as a form of osteopetrosis milder than ARO, identified in childhood due to fractures after minor trauma, characteristic skeletal radiographic changes found accidentally, mild anaemia and occasional visual impairment.…”

Section: Introductionmentioning

confidence: 65%

“…In particular, extrusion of chloride anions is required to neutralize the electric current generated by the H + -ATPase. In this regard, a few years ago it was shown that ClC-7 plays a fundamental role in osteoclast physiology, as demonstrated by the severe osteopetrotic phenotype displayed by the clc7 -/-mouse model (Kornak et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…CLCN7-dependent ARO is usually diagnosed at birth or early in infancy due to generalized osteosclerosis and severe haematological deficits; primary neurological defects, such as cerebral and retinal atrophy, are often present and are displayed also by the knockout mouse (Kornak et al, 2001;Frattini et al, 2003;Kasper et al, 2005). This form is frequently lethal in early life, despite haematological reconstitution by haematopoietic stem cell transplantation (HSCT).…”

Section: Introductionmentioning

confidence: 99%

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Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations

et al. 2010

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ABSTRACT:The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.

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Section: Introductionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations

et al. 2010

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“…(1,(5)(6)(7)(8)(9)(10) The SNX10 gene was amplified using primers and conditions kindly provided by Aker and colleagues (Hebrew University Medical Center, Jerusalem). The mutation nomenclature conforms to www.hgvs.org/mutnomen.…”

Section: Molecular Studiesmentioning

confidence: 99%

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity

Pangrazio

Fasth

Sbardellati

et al. 2012

Journal of Bone and Mineral Research

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Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in the TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than one-half of ARO cases. Since then, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the sorting nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in 3 consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in three cases of ''Västerbottenian osteopetrosis,'' named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10-dependent ARO constitutes 4% of the cases, with a frequency comparable to the receptor activator of NF-kB ligand (RANKL), receptor activator of NF-kB (RANK) and osteopetrosisassociated transmembrane protein 1 (OSTM1)-dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by hematopoietic stem cell transplantation (HSCT). These results confirm the involvement of the SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases. Further analyses will help to better understand the role of SNX10 in osteoclast physiology and verify whether this protein might be considered a new target for selective antiresorptive therapies. ß

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“…These proteins are structurally related to the omega family of glutathione S-transferases, and are required for development in C. elegans [Berry et al, 2003]. However, trans-genic mice deficient in an unrelated and also widely expressed chloride transporter, CLCN7 [Brandt and Jentsch, 1995], are osteopetrotic [Cleiren et al, 2001;Kornak et al, 2001]. Polymorphisms in CLCN7 are associated with osteopet-rosis in several families as reported in a number of studies [Blair et al, 2004].…”

Section: Bulk Calcium Transport By the Osteoclastmentioning

confidence: 99%

Calcium Signalling and Calcium Transport in Bone Disease

Blair

Schlesinger

Huang

et al.

Subcellular Biochemistry

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Calcium transport and calcium signalling mechanisms in bone cells have, in many cases, been discovered by study of diseases with disordered bone metabolism. Calcium matrix deposition is driven primarily by phosphate production, and disorders in bone deposition include abnormalities in membrane phosphate transport such as in chondrocalcinosis, and defects in phosphate-producing enzymes such as in hypophosphatasia. Matrix removal is driven by acidification, which dissolves the mineral. Disorders in calcium removal from bone matrix by osteoclasts cause osteopetrosis. On the other hand, although bone is central to management of extracellular calcium, bone is not a major calcium sensing organ, although calcium sensing proteins are expressed in both osteoblasts and osteoclasts. Intracellular calcium signals are involved in secondary control including cellular motility and survival, but the relationship of these findings to specific diseases is not clear. Intracellular calcium signals may regulate the balance of cell survival versus proliferation or anabolic functional response as part of signalling cascades that integrate the response to primary signals via cell stretch, estrogen, tyrosine kinase, and tumor necrosis factor receptors Keywords Hypophosphatasia; chondrocalcinosis; osteopetrosis; osteoporosis Although bone is not considered a major calcium sensing organ in humans, the cells of bone tissue control over 99% of the human body's calcium content. The principal calcium sensors that regulate bone calcium uptake and release are in the parathyroid glands. Bone function is also modified by vitamin D and by calcium transport in the kidney and intestine. These indirect mechanisms of controlling bone calcium metabolism are beyond the scope of our considerations here. In spite of processing such massive quantities of the Ca 2+ bone cells use calcium in their homeostatic control processes. The massive movement of calcium is carried out by specialized and regulated transporters. Defects in the transporters cause diseases with affect bone structure or function. Indeed, inborn errors have been very important in defining the calcium transport mechanisms in bone.Additionally, calcium is used by bone forming and bone degrading cells as a secondary mediator of hormone and cytokine action. These actions include roles in intercellular communication within groups of osteoblasts, which are connected by gap junctions [Henriksen et al., 2006]. These osteoblast groups function in a coordinated fashion in bone synthesis and maintenance, and are collectively known as the osteon. Osteoblasts in these groups are connected by gap junctions which are capable of propagating signals in the cell groups, including calcium waves [Xia and Ferrier, 1992]. Calcium is also an important regulator of

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Loss of the ClC-7 Chloride Channel Leads to Osteopetrosis in Mice and Man

Cited by 906 publications

References 39 publications

Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations

Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity

Calcium Signalling and Calcium Transport in Bone Disease

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