Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia

Xue, Yan; Wang, Weiguang; Mao, Tianqiu; Duan, Xiaohong

doi:10.1016/j.jcms.2011.07.014

Cited by 26 publications

(24 citation statements)

References 25 publications

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“…Other features typical for this condition described in human and mouse were also noticed in calves, including abnormal skull shape, small body size and visual deficiency or blindness due to retinal degeneration (listed in supplementary material Table S1). The striking gingival hamartomas displayed by the majority of mutant calves might be related to an impaired tooth eruption, which has been described for ClC-7 knockout mice (Kornak et al, 2001) and in anecdotal reports of small odontomas in human patients (Luzzi et al, 2006; Xue et al, 2012). Accordingly, the invariable location of the hamartoma on the lower jaw may be related to the absence of canine and incisor teeth on the upper jaw in cattle.…”

Section: Resultsmentioning

confidence: 91%

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle

Sartelet

Stauber

Coppieters

et al. 2013

Disease Models &Amp; Mechanisms

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Chloride-proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage-dependent gating of ClC-7/Ostm1. However, it has remained unclear whether the fastened kinetics is indeed causative for the disease. Here we identified and characterized a new deleterious ClC-7 mutation in Belgian Blue cattle with a severe symptomatology including perinatal lethality and in most cases gingival hamartomas. By autozygosity mapping and genome-wide sequencing we found a handful of candidate variants, including a cluster of three private SNPs causing the substitution of a conserved tyrosine in the CBS2 domain of ClC-7 by glutamine. The case for ClC-7 was strengthened by subsequent examination of affected calves that revealed severe osteopetrosis. The Y750Q mutation largely preserved the lysosomal localization and assembly of ClC-7/Ostm1, but drastically accelerated its activation by membrane depolarization. These data provide first evidence that accelerated ClC-7/Ostm1 gating per se is deleterious, highlighting a physiological importance of the slow voltage-activation of ClC-7/Ostm1 in lysosomal function and bone resorption.

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Section: Resultsmentioning

confidence: 91%

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle

Sartelet

Stauber

Coppieters

et al. 2013

Disease Models &Amp; Mechanisms

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“…In humans, however, only two forms of clearly hereditary malformations of the roots alone seem to exist. The first one is associated with osteopetrosis due to genetic defects of CLCN7 (encoding a chloride channel component; Xue et al, 2012 ), the second one is related to a defective PLG gene (encoding plaminogen; Tananuvat et al, 2014 ). In the absence of confirming evidence, both conditions thus far constitute isolated cases.…”

Section: Introductionmentioning

confidence: 99%

Malformations of the tooth root in humans

Luder

2015

Front. Physiol.

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The most common root malformations in humans arise from either developmental disorders of the root alone or disorders of radicular development as part of a general tooth dysplasia. The aim of this review is to relate the characteristics of these root malformations to potentially disrupted processes involved in radicular morphogenesis. Radicular morphogenesis proceeds under the control of Hertwig's epithelial root sheath (HERS) which determines the number, length, and shape of the root, induces the formation of radicular dentin, and participates in the development of root cementum. Formation of HERS at the transition from crown to root development appears to be very insensitive to adverse effects, with the result that rootless teeth are extremely rare. In contrast, shortened roots as a consequence of impaired or prematurely halted apical growth of HERS constitute the most prevalent radicular dysplasia which occurs due to trauma and unknown reasons as well as in association with dentin disorders. While odontoblast differentiation inevitably stops when growth of HERS is arrested, it seems to be unaffected even in cases of severe dentin dysplasias such as regional odontodysplasia and dentin dysplasia type I. As a result radicular dentin formation is at least initiated and progresses for a limited time. The only condition affecting cementogenesis is hypophosphatasia which disrupts the formation of acellular cementum through an inhibition of mineralization. A process particularly susceptible to adverse effects appears to be the formation of the furcation in multirooted teeth. Impairment or disruption of this process entails taurodontism, single-rooted posterior teeth, and misshapen furcations. Thus, even though many characteristics of human root malformations can be related to disorders of specific processes involved in radicular morphogenesis, precise inferences as to the pathogenesis of these dysplasias are hampered by the still limited knowledge on root formation.

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“…Certain missense mutations in one allele of CLCN7 gene lead to autosomal dominant osteopetrosis type 2 (ADO2, Albers-Schonberg disease), a milder and the most common form of osteopetrosis with symptoms not evident until later in life (Cleiren et al, 2001; Del Fattore et al, 2008). Not surprisingly, lack of tooth eruption has been reported in both Clcn7 −/− mice (Kornak et al, 2001) and in patients with CLCN7 gene mutations (Xue et al, 2012; Duan, 2014); this is because tooth eruption is critically dependent on osteoclast activity to reabsorb surrounding alveolar bone, which enables root development and the crown of the tooth to erupt into the oral cavity.…”

Section: Introductionmentioning

confidence: 99%

Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7

Wen

Lacruz

Paine

2015

The Anatomical Record

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ClC-7 is a 2Cl−/1H+-exchanger expressed at late endosomes and lysosomes, as well as the ruffled border of osteoclasts. ClC-7 deficiencies in mice and humans lead to impaired osteoclast function and therefore osteopetrosis. Failure of tooth eruption is also apparent in ClC-7 mutant animals, and this has been attributed to the osteoclast dysfunction and the subsequent defect in alveolar bone resorptive activity surrounding tooth roots. Ameloblasts also express ClC-7, and this study aims to determine the significance of ClC-7 in enamel formation by examining the dentitions of ClC-7 mutant mice. Micro-CT analysis revealed that the molar teeth of 3-week old ClC-7 mutant mice had no roots, and the incisors were smaller than their age-matched controls. Despite these notable developmental differences, the enamel and dentin densities of the mutant mice were comparable to those of the wild type littermates. Scanning electron microscopy (SEM) showed normal enamel crystallite and prismatic organization in the ClC-7 mutant mice, although the enamel was thinner (hypoplastic) than in controls. These results suggested that ClC-7 was not critical to enamel and dentin formation, and the observed tooth defects may be related more to a resulting alveolar bone phenotype. Micro-CT analysis also revealed abnormal features in the calvarial bones of the mutant mice. The cranial sutures in ClC-7 mutant mice remained open compared to the closed sutures seen in the control mice at 3 weeks. These data demonstrate that ClC-7 deficiency impacts the development of the dentition and calvaria, but does not significantly disrupt amelogenesis.

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Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia

Cited by 26 publications

References 25 publications

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle

Malformations of the tooth root in humans

Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7

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Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia

Cited by 26 publications

References 25 publications

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle

A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle

Malformations of the tooth root in humans

Dental and Cranial Pathologies in Mice Lacking the Cl−/H+‐Exchanger ClC‐7

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Dental and Cranial Pathologies in Mice Lacking the Cl⁻/H⁺‐Exchanger ClC‐7