Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor and Downstream Effector Molecules

Silve, Caroline; Jüppner, Harald

doi:10.1016/b978-0-12-397166-1.00040-0

Cited by 4 publications

(3 citation statements)

References 154 publications

(173 reference statements)

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“…( 1 , 2 , 3 ) Thus far, five different PTH1R mutations have been identified in JMC patients that affect one of three different amino acid residues, His223, Thr410, and Ile458, located at the intracellular portion of transmembrane helix 2, 6, and 7, respectively. ( 4 , 5 ) The JMC mutations lead to constitutive, agonist‐independent cAMP formation, as measured in cell‐based assays in vitro. ( 5 , 6 ) This agonist‐independent activity of the mutant PTH1R leads in patients to marked growth plate abnormalities, which resemble radiographically those seen in patients with severe rickets.…”

Section: Introductionmentioning

confidence: 99%

“…( 15 , 16 ) Severe skeletal changes and life‐long evidence for hypercalcemia and/or hypercalciuria are thus hallmarks encountered in most JMC patients. ( 4 , 17 , 18 ) However, one JMC patient with the most frequent H223R mutation revealed, possibly because of mosaicism, no overt hypercalcemia or hypophosphatemia. ( 18 ) Furthermore, the T410R mutation in the PTH1R causes a less severe form of the disease without obvious serum calcium and phosphate abnormalities and heights that are at the lower end of the normal range.…”

Section: Introductionmentioning

confidence: 99%

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Substantially Delayed Maturation of Growth Plate Chondrocytes in “Humanized” PTH1R Mice with the H223R Mutation of Jansen's Disease

et al. 2023

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Activating parathyroid hormone (PTH)/PTH‐related Peptide (PTHrP) receptor (PTH1R) mutations causes Jansen's metaphyseal chondrodysplasia (JMC), a rare disease characterized by growth plate abnormalities, short stature, and PTH‐independent hypercalcemia. Previously generated transgenic JMC mouse models, in which the human PTH1R allele with the H223R mutation (H223R‐PTH1R) is expressed in osteoblasts via type Ia1 collagen or DMP1 promoters cause excess bone mass, while expression of the mutant allele via the type IIa1 collagen promoter results in only minor growth plate changes. Thus, neither transgenic JMC model adequately recapitulates the human disease. We therefore generated “humanized” JMC mice in which the H223R‐PTH1R allele was expressed via the endogenous mouse Pth1r promoter and, thus, in all relevant target tissues. Founders with the H223R allele typically died within 2 months without reproducing; several mosaic male founders, however, lived longer and produced F1 H223R‐PTH1R offspring, which were small and exhibited marked growth plate abnormalities. Serum calcium and phosphate levels of the mutant mice were not different from wild‐type littermates, but serum PTH and P1NP were reduced significantly, while CTX‐1 and CTX‐2 were slightly increased. Histological and RNAscope analyses of the mutant tibial growth plates revealed markedly expanded zones of type II collagen‐positive, proliferating/prehypertrophic chondrocytes, abundant apoptotic cells in the growth plate center and a progressive reduction of type X collagen‐positive hypertrophic chondrocytes and primary spongiosa. The “humanized” H223R‐PTH1R mice are likely to provide a more suitable model for defining the JMC phenotype and for assessing potential treatment options for this debilitating disease of skeletal development and mineral ion homeostasis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Substantially Delayed Maturation of Growth Plate Chondrocytes in “Humanized” PTH1R Mice with the H223R Mutation of Jansen's Disease

et al. 2023

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“…Csukasi et al showed that mutations in the PTH receptor-1 (PTH1R) affect the differentiation of skeletal progenitors and lead to accumulation of fat or cartilage in bones in the autosomal dominant Jansen Metaphyseal Chondrodysplasia (JMC) and the autosomal recessive Blomstrand Chondrodysplasia (BOCD). JMC is a rare skeletal dysplasia characterized by abnormal endochondral bone formation and typically severe hypercalcemia due to delayed chondrocyte and bone formation ( Gram et al, 1959 ; Silve and Jüppner, 2015 ); BOCD is a neonatal osteosclerotic dysplasia characterized by advanced endochondral bone maturation, very short limbs, dwarfism and prenatal lethality ( Blomstrand et al, 1985 ; Jobert et al, 1998 ; Jüppner and Thakker, 2008 ; Hochberg, 2019 ). Csukasi et al dissected the mechanisms by which skeletal progenitors differentiate towards bone or fat involving a pathway regulated by DEP-domain containing mTOR-interacting protein (DEPTOR) in a mTOR independent manner and TAZ protein.…”

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Editorial: Identification of New Molecular Mechanisms of Bone Disease, volume II

Coudert

Battafarano²,

Fattore³

2023

Front. Cell Dev. Biol.

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In the last years, the identification of new biomarkers to perform a correct and opportune diagnosis of bone diseases has been a great interest in the field. Although many bone biomarkers have been identified, so far only two serum makers have been recognized as relevant for diagnostic purposes: CTX (C-terminal telopeptide of type I collagen) as a marker of bone resorption and P1NP (N-terminal propeptide of type I procollagen) as sign of bone formation (Vasikaran et al., 2011). However, the measurement of these two molecules is not sufficient to perform early diagnosis and to set a therapeutic plan for some bone diseases.Indeed, the lack of effective biomarkers makes difficult to achieve the prompt diagnosis and intervention for osteonecrosis of the femoral head (ONFH). In their paper here published, Liu et al. described the lncRNA (Long Non-coding RNA) growth arrestspecific transcript 5 (GAS5) as a potential biomarker for ONFH early diagnosis. The authors found that the expression of lncRNA GAS5 was significantly downregulated in patients with ONFH; this result was also confirmed in a rat model of ONFH. The relevance of lncRNA GAS5 in the bone remodeling activity was demonstrated by its increased expression during osteoblast differentiation and by its downregulation in osteoporosis patients and mice (Feng et al., 2019;Li et al., 2020). The key role of long non-coding RNA in the regulation of bone remodeling was also described in the paper published by Hu et al.; in their study, the authors identified an upregulation of Gm15222 and a positive correlation between its levels and BMP4 in diet induced obese (DIO) mice. Moreover, they demonstrated that Gm15222 promotes osteogenesis and inhibits the expression of adipogenesis-related genes in DIO by epigenetic mechanisms involving the recruitment of lysine demethylases KDM6B and KDM4B, respectively.A prompt diagnosis is particularly important for rare bone diseases such as primary thyroid osteosarcoma. In this Research Topic, Wang et al. identified KMT2C mutation as a potential diagnostic molecular marker. KMT2C encodes histone methyltransferase, which regulates gene transcription by modifying chromatin structure. KMT2C exerts a relevant role in embryonic development and cell proliferation. Interestingly, mutations of KMT2C were reported in 87% of osteosarcoma patients, suggesting its key role in bone carcinogenesis. Wang and coworkers described four variants of KMT2C mutations in a 72-year-old woman with primary thyroid osteosarcoma and discussed the relevance to

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Pseudohypoparathyroidism Type Ib (PHP-Ib): PTH-Resistant Hypocalcemia and Hyperphosphatemia Due to Abnormal GNAS Methylation

Jüppner

2015

Hypoparathyroidism

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Genetic Disorders Caused by Mutations in the PTH/PTHrP Receptor and Downstream Effector Molecules

Cited by 4 publications

References 154 publications

Substantially Delayed Maturation of Growth Plate Chondrocytes in “Humanized” PTH1R Mice with the H223R Mutation of Jansen's Disease

Substantially Delayed Maturation of Growth Plate Chondrocytes in “Humanized” PTH1R Mice with the H223R Mutation of Jansen's Disease

Editorial: Identification of New Molecular Mechanisms of Bone Disease, volume II

Pseudohypoparathyroidism Type Ib (PHP-Ib): PTH-Resistant Hypocalcemia and Hyperphosphatemia Due to Abnormal GNAS Methylation

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