Constitutively Activated Receptors for Parathyroid Hormone and Parathyroid Hormone–Related Peptide in Jansen's Metaphyseal Chondrodysplasia

Schipani, Ernestina; Langman, Craig B.; Parfitt, A. M.; Jensen, Geoffrey S.; Kikuchi, Shinichi; Kooh, Sang Whay; Cole, William G.; Jüppner, Harald

doi:10.1056/nejm199609053351004

Cited by 283 publications

(151 citation statements)

References 27 publications

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“…The mis-sense mutation at the junction between the PTH/PTHrP receptor's first intracellular loop and transmembrane helix 2 changing a histidine residue at position 223 to Arginine was the same as that reported by Schipani et al in four Caucasian patients by direct sequencing of exon M2 (helix 2) genomic DNA [7,8]. But we found that the fibroblast PTH/PTHrP receptor cDNA predominantly expressed an abnormal allele despite the fact that examination of genomic DNA containing this region revealed a heterozygous nucleotide change in the exon M2 of the gene.…”

Section: Discussionsupporting

confidence: 71%

“…At that time, serum PTH levels were normal in two assay systems, and urine cAMP excretion tended to be high. Hypercalcemia was treated by oral phosphorus administration or calcitonin infusion from age 3 mo to 11 yr. At age 9 yr, the serum PTHrP level was undetectable (less than 0.2 ng/ ml) [8]. Progressive widening, splaying and fragmentation of the metaphyses, detected by radiography, resulted in shortened tubular bones and consequent short stature 107 cm (-6.5 SD) with an upper/lower segement ratio of 1.49 at age 13 yr (Fig.…”

Section: Methodsmentioning

confidence: 95%

“…Since the patient's clinical data are compatible with the notion of activation of the PTH/PTHrP receptor without its ligand(s), we examined his PTH/PTHrP receptor complementary DNA (cDNA) and identified His22 -Arg substitution in the cDNA. We also compared age-related changes in the widespread abnormalities with five other JMC patients, since just before the submission of this manuscript, Juppner et al reported five JMC patients with the His223-Arg or T410P substitution in the PTH/PTHrP receptor gene [7,8].…”

mentioning

confidence: 99%

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Jansen-type Metaphyseal Chondrodysplasia: Analysis of PTH/PTH-related Protein Receptor Messenger RNA by the Reverse Transcriptase-Polymerase Chain Method.

et al. 1997

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Abstract. Jansen-type metaphyseal chondrodysplasia (JMC) has both delayed ossification in long bones and usually hypercalcemia. We report a Japanese male patient with JMC who presented with rachitic signs on radiographs, hypercalcemia (13 mg/dl) and low %TRP at age 3 months (mo). Hypercalcemia was treated from age 3 mo to 11 yr. Progressive widening, splaying and fragmentation of the metaphyses have been recognized on radiographs which resulted in shortened tubular bones and consequent short stature [107 cm (-6.5 SD)] at age 13 yr. Hypercalcemia tended to normalize, and %TRP became normal at age 13 yr. Repeated measurements of serum PTH and PTH-related protein (PTHrP) levels showed that they were low or normal in the face of hypercalcemia and high urine cAMP excretion, which led us to suspect constitutive activation of the PTH/PTHrP receptor. Direct sequencing of PTH/PTHrP receptor complementary DNA from skin fibroblast cells revealed a CAC to CGC transversion yielding a strictly conserved His223 to Arg substitution found in 90% of DNA fragment in the second transmembrane domain of the receptor. This mutation created a restriction site SpM (C l CATG/C).Direct sequencing of genomic DNA and also restriction enzyme digestion revealed heterozygous transition. The mutation was absent in the parents with normal phenotype. We conclude that both dysplastic bone lesions and calcium homeostasis are age-dependent in JMC, and that the His223-Arg substitution is the same as that found in four Caucasian patients with a similar phenotype irrespective of the ethnic difference, and that the preferential expression of an abnormal allele of the PTH/PTHrP receptor mRNA in skin fibroblast despite heterogygotic transversion in the genomic DNA suggests the importance of allele expression. [3,4]. We first determined PTH-PTHrP levels in relation to urine cAMP excretion and serum and urine markers relating to bone resorption and formation in a Japanese patient with this condition. The PTH/PTHrP receptor belongs to a family of G protein-coupled receptors with signaling properties of both cAMP and Ca2+ [5,6]. Since the patient's clinical data are compatible with the notion of activation of the PTH/PTHrP receptor without its

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Section: Discussionsupporting

confidence: 71%

Section: Methodsmentioning

confidence: 95%

mentioning

confidence: 99%

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Jansen-type Metaphyseal Chondrodysplasia: Analysis of PTH/PTH-related Protein Receptor Messenger RNA by the Reverse Transcriptase-Polymerase Chain Method.

et al. 1997

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“…Such a pattern raises the possibility of a pathogenic role for pathways that involve molecules that exert different effects before and after birth, such as parathyroid hormone-related peptide (PTHrP). Although such mechanisms might be unclear, alterations in the manifestations of bone disease beyond early life are recognized in other conditions, such as Jansen metaphyseal chondrodysplasia, which is caused by constitutive activation of the PTHrP receptor (7) ; in that case, there is an evolution of the metaphyseal abnormalities from a rickets-like appearance in infancy to one of metaphyseal lucency and cortical thickening. (8) …”

Section: Discussionmentioning

confidence: 99%

Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: Clues to pathogenesis

Arundel

Offiah

Bishop

2010

Journal of Bone and Mineral Research

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We present the first report of the development of characteristic radiologic appearances of long bones during the first year of life in an infant with type V osteogenesis imperfecta (OI). We show the evolution of metaphyseal abnormalities from a rickets-like appearance to the classically described dense metaphyseal bands. These abnormalities suggest that the underlying defect in type V OI may involve a molecule common to both bone and cartilage that is involved in the regulation of growth plate development and metadiaphyseal ossification. Our findings provide new insights into skeletal development in type V OI and potentially yield useful clues to the identity of the defect underpinning the condition. ß

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“…De fato, 3 mutações inativadoras do gene do receptor de PTH/PTHrp (H223R, T410P e I458R) já foram descritas em 11 pacientes não relacionados portadores desta doença, confirmando esta associação causal (55,(72)(73)(74). A identificação desta associação (assim como a associação entre condrodisplasia de Blomstrand e inativação deste mesmo receptor) tem implicações para a melhor compreensão da importân-cia biológica do receptor de PTH/PTHrp no que diz respeito ao desenvolvimento esquelético humano, além do papel que exerce na regulação homeostática mineral.…”

Section: B -Doenças Endócrinas Causadas Por Mutações Ativadoras (Tabeunclassified

Receptores acoplados à proteína G: implicações para a fisiologia e doenças endócrinas

Hauache

2001

Arq Bras Endocrinol Metab

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Arq Bras Endocrinol Metab vol 45 nº 3 Junho 2001 228 RESUMOA maioria dos hormônios polipeptídicos e mesmo o cálcio extracelular atuam em suas células-alvo através de receptores acoplados à proteí-na G (GPCRs). Nos últimos anos, tem sido freqüente a identificação e associação causal de mutações em proteínas G e em GPCRs com diversas endocrinopatias, como diabetes insipidus nefrogênico, hipotiroidismo familiar, puberdade precoce familiar no sexo masculino e nódulos tiroidianos hiperfuncionantes. Nesta revisão, abordamos aspectos referentes ao mecanismo de transdução do sinal acoplado à proteína G, e descrevemos como mutações em GPCRs podem levar a algumas doenças endócrinas. Finalmente, comentamos a respeito das implicações diagnósticas e terapêuticas associadas com o maior conhecimento dos GPCRs. ABSTRACTThe majority of polypeptide hormones and even extracellular calcium signal their target cells through G protein-coupled receptors (GPCRs). Recently, many mutations have been both identified and associated with several endocrine disorders, such as nephrogenic diabetes insipidus, familial hypothyroidism, familial male precocious puberty and sporadic hyperfunctional thyroid nodules. In this review, the G-protein coupled signal transduction mechanism is described. Moreover, the mechanism through which GPCRs' mutations lead to endocrine disease is reviewed. Finally, we will comment on implications for diagnosis and treatment related to increasing research on GPCRs. Considerações Gerais Sobre a Proteína G, Receptores Acoplados à Proteína G e o Ciclo da GTPaseA S PROTEÍNAS GS INTERMEDIAM A TRANSMISSÃO do sinal entre os receptores acoplados às proteínas Gs (GPCRs) e efetores múltiplos, tais como enzimas e canais iônicos. Os genes que codificam as proteínas Gs são membros de uma superfamília de genes que codificam proteínas que se ligam a nucleotídeos guanina com alta afinidade e especificidade (1). As proteínas Gs são heterotrímeras, constituídas pelas sub-unidades α, β e γ. A sub-unidade a se liga aos nucleotídeos guanina enquanto as subunidades β e γ formam um dímero, através de uma ligação não covalente mas suficientemente forte para funcionar como uma unidade (2). Já foram descritos 16 genes para as sub-unidades α, com graus de expressão e especificidade de ligação ao receptor e ao efetor variáveis. As proteínas Gs são intermediárias essenciais para o mecanismo de transdução de sinal, ligando-se a diversos GPCRs, localizados na superfície celular (3).

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Constitutively Activated Receptors for Parathyroid Hormone and Parathyroid Hormone–Related Peptide in Jansen's Metaphyseal Chondrodysplasia

Abstract: The expression of constitutively active PTH-PTHrp receptors in kidney, bone, and growth-plate chondrocytes provides a plausible genetic explanation for mineral-ion abnormalities and metaphyseal changes in patients with Jansen's disease.

Cited by 283 publications

References 27 publications

Jansen-type Metaphyseal Chondrodysplasia: Analysis of PTH/PTH-related Protein Receptor Messenger RNA by the Reverse Transcriptase-Polymerase Chain Method.

Jansen-type Metaphyseal Chondrodysplasia: Analysis of PTH/PTH-related Protein Receptor Messenger RNA by the Reverse Transcriptase-Polymerase Chain Method.

Evolution of the radiographic appearance of the metaphyses over the first year of life in type V osteogenesis imperfecta: Clues to pathogenesis

Receptores acoplados à proteína G: implicações para a fisiologia e doenças endócrinas

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