The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3

Jüppner, Harald; Schipani, Ernestina; Baştepe, Murat; Cole, David E. C.; Lawson, Margaret L.; Mannstadt, Michael; Hendy, Geoffrey N.; Plotkin, Horacio; Koshiyama, Hiroyuki; T, Koh; Crawford, John D.; Olsen, Bjørn R.; Vikkula, Miikka

doi:10.1073/pnas.95.20.11798

Cited by 182 publications

(167 citation statements)

References 49 publications

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“…The PTH receptor is normal in both disorders (39). Both PHP1A and 1B are inherited as autosomal dominant and, in pedigree linkage analysis, both map to the same locus on chromosome 20q13.3 (40). Of interest to the study of imprinting, both are transmitted only from the mother (40,41).…”

Section: Pseudohypoparathyroidism and Albright Hereditary Osteodystrophymentioning

confidence: 99%

“…However, members of PHP1B pedigrees never have AHO or multiple hormone resistance, indicating a distinct type of mutation in the same locus (40). The cause of PHP1A was elucidated when inactivating mutations were found on the maternal copy of the GNAS1 gene which encodes an a subunit of the activating G-protein complex (G s a), which couples receptors with seven transmembrane domains (including PTHr) to adenylate cyclase (42).…”

Section: Pseudohypoparathyroidism and Albright Hereditary Osteodystrophymentioning

confidence: 99%

“…Both PHP1A and 1B are inherited as autosomal dominant and, in pedigree linkage analysis, both map to the same locus on chromosome 20q13.3 (40). Of interest to the study of imprinting, both are transmitted only from the mother (40,41). Different members of the same PHP1A pedigree may have the full PHP1A, or the AHO phenotype alone without PTH resistance (pseudo-pseudohypoparathyroidism), indicating that the same mutation may or may not cause PTH resistance depending on other genetic or environmental Figure 2 Proposed explanation for the paternal origin of germ-line mutations of patients with the focal form of neonatal hyperinsulinism.…”

Section: Pseudohypoparathyroidism and Albright Hereditary Osteodystrophymentioning

confidence: 99%

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Parental genomic imprinting in endocrinopathies

Polychronakos

Kukuvitis

2002

European Journal of Endocrinology

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Genomic imprinting is the phenomenon whereby some genes preferentially produce mRNA transcripts from the gene copy derived from the parent of a specific sex. It has been implicated in a number of human diseases (most of them of endocrine interest), such as Prader -Willi/Angelman syndromes, Silver -Russell syndrome, Beckwith -Wiedemann syndrome, transient neonatal diabetes, the focal form of nesidioblastosis, and pseudohypoparathyroidism. Involvement of imprinted genes affecting birth weight and causing susceptibility to type 1 diabetes is under investigation. Recent knowledge about the varied molecular mechanisms involved will be outlined.

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Section: Pseudohypoparathyroidism and Albright Hereditary Osteodystrophymentioning

confidence: 99%

Section: Pseudohypoparathyroidism and Albright Hereditary Osteodystrophymentioning

confidence: 99%

Section: Pseudohypoparathyroidism and Albright Hereditary Osteodystrophymentioning

confidence: 99%

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Parental genomic imprinting in endocrinopathies

Polychronakos

Kukuvitis

2002

European Journal of Endocrinology

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“…The first classification system distinguished PHP variants as PHP1A, PHP1B, PHP1C and PPHP 1,2,27,29,69,132,133 . The subtype assignment is based on the presence or absence of AHO together with characterization of hormone resistance and determination of G s α protein activity using in vitro assays 132,133 .…”

Section: Evolution Of Php Classificationmentioning

confidence: 99%

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Mantovani¹,

Lecumberri²,

Baştepe³

et al. 2018

EJEA

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Pseu do hy popar ath yroi dism (PHP) and related disorders are associated with a spectrum of abnormal physical characteristics as well as neurocognitive and endocrine abnormalities that are caused primarily by molecular defects that impair hormonal signalling via receptors that are coupled, through the α-subunit of the stimulatory G protein (G s α), to activation of adenylyl cyclase (Fig. 1). 6,7,20,48 * Abstract | This Consensus Statement covers recommendations for the diagnosis and management of patients with pseu do hy popar ath yroi dism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency , hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

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“…Estudos recentes têm demonstrado resistência ao PTH, somente quando a herança é materna semelhante aos casos de PHP Ia. Em quatro pacientes o mapeamento genético associou a doença à região 20q1.3 que abriga o gene GNAS1 (43)(44). Nenhuma mutação foi descrita no receptor do PTH e uma única mutação foi descrita no exon 13 do gene GNAS1, responsável pela interação da proteína Gsα com o receptor, em três irmãos com PHP Ib.…”

Section: Defeito Do Imprinting Do Gene Gnas1 No Pseudohipoparatireioiunclassified

Manifestações Endócrinas das Mutações da Proteína Gsalfae do Imprinting do Gene GNAS1

Fragoso

2002

Arq Bras Endocrinol Metab

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RESUMOEsta revisão resume o papel da patogênese molecular das mutações do gene da proteína G s α em doenças endócrinas. As proteínas G transmitem o sinal celular de receptores de membrana 7TM. Este sistema pode ser ativado por fotons de luz, odorantes e hormônios (LH, FSH, TSH, PTH, etc). Seu efetor é a adenilato-ciclase que induz a formação de AMPc. A proteína G inativa é heterotrimérica e associada ao GDT. Receptores que ativam a proteína G s α dissociam o GDT para GTP, enquanto a atividade intrínseca GTPase hidrolisa o GTP, mantendo a proteína G s α no estado inativo, ligado ao GDP. Mutações no gene GNAS1, que codifica a proteína G s α, alteram sítios altamente conservados (Arg 201 e Gln 227 ), críticos para a atividade GTPase, levando à ativação constitutiva do sinal celular. Tais mutações são encontradas em raros tumores endócrinos, na fibrodisplasia óssea e na síndrome de McCune Albright. Ao contrário, mutações inativadoras podem levar à osteodistrofia hereditária de Albright, se transmitidas pelo alelo paterno e pseudohipoparatireoidismo tipo Ia, se transmitidas pelo alelo materno. Em ratas com knockout, o gene Gnas sofre o fenômeno de imprinting tecido específico. Em tumores de hipófise, o gene GNAS1 também sofre imprinting com expressão preferencial do alelo materno. No pseudohipoparatireoidismo tipo Ib, um defeito do imprinting na região promotora do exon 1A do gene GNAS1 parece justificar a resistência renal isolada ao PTH. Estes exemplos ilustram como defeitos da proteína G s α podem ser responsáveis pela patogênese molecular de diferentes doenças endócrinas.

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The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3

Cited by 182 publications

References 49 publications

Parental genomic imprinting in endocrinopathies

Parental genomic imprinting in endocrinopathies

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

Manifestações Endócrinas das Mutações da Proteína Gsalfae do Imprinting do Gene GNAS1

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