Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C&gt;T mutation in CLCN7

Chen, Xiang; Zhang, Kun; Hock, Janet M.; Wang, Qianqian; Yu, Xijie

doi:10.1038/boneres.2016.35

Cited by 16 publications

(11 citation statements)

References 33 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that perturbation of lysosomal function leads to alterations in the activity of cathepsin proteases such as CTSK. Not surprisinggly, we detected a remarkable decrease of CTSK in clcn7 morphants ( Figure 6B ), which was consistent with the previous report regarding the reduced expression of CTSK mRNA in ADO II patient 37.…”

Section: Resultssupporting

confidence: 93%

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

Ji¹,

Li²,

Yang³

et al. 2019

Theranostics

View full text Add to dashboard Cite

Human CLCN7 encodes voltage-gated chloride channel 7 (ClC-7); mutations of CLCN7 lead to osteopetrosis which is characterized by increased bone mass and impaired osteoclast function. In our previous clinical practice, we noticed that osteopetrosis patients with CLCN7 mutations had some special deformities in craniofacial morphology and tooth dysplasia. It is unclear whether these phenotypes are the typical features of CLCN7 involved osteopetrosis and whether ClC-7 could regulate the development of craniofacial bone and tooth in some signaling pathways. Methods : First, we collected 80 osteopetrosis cases from the literature and compared their craniofacial and dental phenotypes. Second, four osteopetrosis pedigrees with CLCN7 mutations were recruited from our clinic for gene testing and clinical analysis of their craniofacial and dental phenotypes. Third, we used a zebrafish model with clcn7 morpholino treatment to detect the effects of ClC-7 deficiency on the development of craniofacial and dental phenotypes. General observation, whole mount alcian blue and alizarin red staining, whole mount in situ hybridization, scanning electron microscope observation, lysoSensor staining, Q-PCR and western blotting were performed to observe the in vivo characteristics of craniofacial bone and tooth changes. Fourth, mouse marrow stromal cells were further primarily cultured to detect ClC-7 related mRNA and protein changes using siRNA, Q-PCR and western blotting. Results: Over 84% of osteopetrosis patients in the literature had some typical craniofacial and tooth phenotypes, including macrocephaly, frontal bossing, and changes in shape and proportions of facial skeleton, and these unique features are more severe and frequent in autosomal recessive osteopetrosis than in autosomal dominant osteopetrosis patients. Our four pedigrees with CLCN7 mutations confirmed the aforementioned clinical features. clcn7 knockdown in zebrafish reproduced the craniofacial cartilage defects and various dental malformations combined the decreased levels of col10a1 , sp7 , dlx2b , eve1 , and cx43 . Loss of clcn7 function resulted in lysosomal storage in the brain and jaw as well as downregulated cathepsin K (CTSK). The craniofacial phenotype severity also presented a dose-dependent relationship with the levels of ClC-7 and CTSK. ClC-7/CTSK further altered the balance of TGF-β/BMP signaling pathway, causing elevated TGF-β-like Smad2 signals and reduced BMP-like Smad1/5/8 signals in clcn7 morphants. SB431542 inhibitor of TGF-β pathway partially rescued the aforementioned craniofacial bone and tooth defects of ...

show abstract

Section: Resultssupporting

confidence: 93%

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

Ji¹,

Li²,

Yang³

et al. 2019

Theranostics

View full text Add to dashboard Cite

show abstract

“…Precursor cells of osteoclasts (OCs) from human peripheral blood were cultured as previously described . A 15 mL of heparin anticoagulated peripheral blood was obtained by venipuncture from the patient, and a healthy age‐ and sex‐matched control.…”

Section: Methodsmentioning

confidence: 99%

A paternally inherited non‐sense variant c.424G>T (p.G142) in the first exon of XLαs* in an adult patient with hypophosphatemia and osteopetrosis

et al. 2020

Self Cite

View full text Add to dashboard Cite

XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotidebinding protein (Gsα), is paternally expressed. The significance of XLαs in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non-sense variant c.424G>T (p. G142*) in the first exon of XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, while possibly having no significant effects on other gene products of this locus. Ellsworth-Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XLαs failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa-B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass. K E Y W O R D S hypophosphatemia, osteopetrosis, parathyroid hormone, pseudohypoparathyroidism, XLαs

show abstract

“…Our in vitro study clearly showed reduced osteoclast formation ability in this patient, 294 which is consistent with the reduced RANKL/OPG ratio. Based on our experience, in 295 vitro osteoclast culture could reliably reflect the osteoclast formation ability of humans 296 [38]. Although this patient had increased CTX levels, we believe he had inhibited bone 297 resorption as a result of decreased osteoclast formation, which is also consistent with formation, leading to increased bone mass ( Figure 5).…”

mentioning

confidence: 83%

A novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas leading to osteopetrosis

chen

Meng

Xie

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

GNAS is one of the most complex gene loci in the human genome and encodes multiple gene products. XLas, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gas), is paternally inherited. Although XLas can mimic the action of Gas, its significance remains largely unknown in humans. Here we report a patient presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone levels. His serum calcium was in the lower limit of normal range. DEXA scan revealed progressive increase in the bone density of this patient. Whole exome sequencing of this subject found a novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas, which was inherited from his father and transmitted to his daughter. This mutation was predicted to exclusively influence the expression of XLas, while may have no significant effects on other gene products of this locus. SaOS2 cells transfected with mutant XLas failed to generate cAMP under parathyroid hormone stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating SOST, DKK1 and OPG levels, while lower RANKL levels and RANKL/OPG ratio, leading to reduced bone resorption. It is speculated that this patient may belong to a very rare type of pseudohypoparathyroidism with selective skeletal resistance but normal renal tubular response to parathyroid hormone. Our findings indicate that XLas plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.

show abstract

Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C>T mutation in CLCN7

Cited by 16 publications

References 33 publications

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

A paternally inherited non‐sense variant c.424G>T (p.G142) in the first exon of XLαs* in an adult patient with hypophosphatemia and osteopetrosis

A novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas leading to osteopetrosis

Contact Info

Product

Resources

About

Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C>T mutation in CLCN7

Cited by 16 publications

References 33 publications

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

A paternally inherited non‐sense variant c.424G>T (p.G142*) in the first exon of XLαs in an adult patient with hypophosphatemia and osteopetrosis

A novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas leading to osteopetrosis

Contact Info

Product

Resources

About

A paternally inherited non‐sense variant c.424G>T (p.G142) in the first exon of XLαs* in an adult patient with hypophosphatemia and osteopetrosis