Autosomal Dominant Pseudohypoparathyroidism Type Ib: A Novel Inherited Deletion Ablating STX16 Causes Loss of Imprinting at the A/B DMR
Francesca Elli,Luisa de Sanctis,Erika Peverelli,Paolo Bordogna,Barbara Pivetta,Gianmaria Miolo,Paolo Beck-Peccoz,Anna Spada,Giovanna Mantovani +8 more
TLDR
This work highlights the importance of performing accurate investigations in PHP-Ib patients with methylation defects to allow precise genetic counseling because, in case of deletions, the segregation ratio is about 50% and the disease phenotype is transmitted in an autosomal dominant fashion via the mother.Abstract:
Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare imprinting disorder characterized by end-organ resistance to PTH and, frequently, to thyroid-stimulating hormone. PHP-Ib familial form, with an autosomal dominant pattern of transmission (autosomal dominant pseudohypoparathyroidism type Ib [AD-PHP-Ib]), is typically characterized by an isolated loss of methylation at the guanine nucleotide-binding protein α-stimulating activity polypeptide 1 A/B differentially methylated region (DMR), secondary to genetic deletions disrupting the upstream imprinting control region in the syntaxin-16 (STX16) locus. However, deletions described up to now failed to account some cases of patients with a methylation defect limited to the A/B DMR; thus, it is expected the existence of other still unknown rearrangements, undetectable with conventional molecular diagnostic methods. Objective: We investigated a PHP-Ib patient with a methylation defect limited to the A/B DMR and no known STX16 deletions to find the underl...read more
Citations
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Journal ArticleDOI
Epidemiology and Diagnosis of Hypoparathyroidism.
Bart L. Clarke,Edward M. Brown,Michael T. Collins,Harald Jüppner,Peter L. Lakatos,Michael A. Levine,Michael Mannstadt,John P. Bilezikian,Anatoly F. Romanischen,Rajesh V. Thakker +9 more
TL;DR: It is important for endocrinologists and other physicians who care for patients with hypoparathyroidism to be aware of recent advances in the epidemiology, diagnosis, and genetics of this disorder.
Journal ArticleDOI
Diagnosis and management of pseudohypoparathyroidism and related disorders: First international Consensus Statement
Giovanna Mantovani,Murat Bastepe,David Monk,Luisa De Sanctis,Susanne Thiele,Alessia Usardi,S Faisal Ahmed,Roberto Bufo,Timothee Choplin,Gianpaolo de Filippo,Guillemette Devernois,Thomas Eggermann,Francesca Elli,Kathleen Freson,Aurora Garcia Ramirez,Emily L. Germain-Lee,Lionel Groussin,Neveen A. T. Hamdy,Patrick Hanna,Olaf Hiort,Harald Jüppner,Peter Kamenický,Nina Knight,Marie Laure Kottler,Elvire Le Norcy,Beatriz Lecumberri,Beatriz Lecumberri,Michael A. Levine,Outi Mäkitie,Regina Matsunaga Martin,Gabriel Á. Martos-Moreno,Masanori Minagawa,Philip Murray,Arrate Pereda,Robert J. Pignolo,Lars Rejnmark,Rebecca Rodado,Anya Rothenbuhler,Vrinda Saraff,Ashley H. Shoemaker,Eileen M. Shore,Caroline Silve,Serap Turan,Philip Woods,M. Carola Zillikens,Guiomar Perez de Nanclares,Agnès Linglart +46 more
TL;DR: A coordinated and multidisciplinary approach from infancy through adulthood is recommended to improve the care of patients affected by pseudohypoparathyroidism and related disorders.
Journal ArticleDOI
GNAS Spectrum of Disorders.
Serap Turan,Murat Bastepe +1 more
TL;DR: The pathogenesis and the phenotypes of these diseases depend significantly on the parental allelic origin of the GNAS mutation, reflecting the tissue-specific paternal Gsα silencing.
Journal ArticleDOI
From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network.
Susanne Thiele,Giovanna Mantovani,Anne Barlier,Valentina Boldrin,Paolo Bordogna,Luisa De Sanctis,Francesca Elli,Kathleen Freson,Intza Garin,Virginie Grybek,Patrick Hanna,Benedetta Izzi,Olaf Hiort,Beatriz Lecumberri,Arrate Pereda,Vrinda Saraff,Caroline Silve,Serap Turan,Alessia Usardi,Ralf Werner,Guiomar Perez de Nanclares,Agnès Linglart +21 more
TL;DR: The EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway called iPPSD, which defines the common mechanism responsible for all diseases and eliminates the clinical or molecular overlap between diseases.
Journal ArticleDOI
Role of DNA methylation in imprinting disorders: an updated review.
TL;DR: The role of DNA methylation in imprinting process is focused on andDNA methylation aberrations in different imprinting disorders are described.
References
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Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins
TL;DR: This work investigates the allelic origin of other mRNAs derived from GNAS1, a gene showing simultaneous imprinting in both the paternal and maternal directions, and finds this gene to be remarkable in the complexity of its allele-specific regulation.
Journal ArticleDOI
The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins.
Bruce E. Hayward,Mamoru Kamiya,Lisa Strain,Veronica Moran,Roderick Campbell,Yoshihide Hayashizaki,David T. Bonthron +6 more
TL;DR: It is shown that, although Gsalpha expression (directed by the promoter upstream of exon 1) is biallelic, GNAS1 is indeed imprinted in a promoter-specific fashion, and may contribute to the anomalous inheritance of PHP Ia.
Journal ArticleDOI
A GNAS1 imprinting defect in pseudohypoparathyroidism type IB
TL;DR: Pseudohypoparathyroidism type IB is associated with a paternal-specific imprinting pattern of the exon 1A region on both alleles, which may lead to decreased G(s)alpha expression in renal proximal tubules.
Journal ArticleDOI
Pseudohypoparathyroidism: Diagnosis and Treatment
TL;DR: This review will focus on PHP type I, in particular its diagnosis, classification, treatment, and underlying molecular alterations.
Journal ArticleDOI
Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib.
Murat Bastepe,Leopold F. Fröhlich,Agnès Linglart,Hilal Abu-Zahra,Katsuyoshi Tojo,Leanne M Ward,Harald Jüppner +6 more
TL;DR: Two kindreds with pseudohypoparathyroidism type Ib report deletions that remove the differentially methylated region encompassing exon NESP55 and exons 3 and 4 of the antisense transcript, suggesting that the deleted region contains a cis-acting element that controls imprinting of the maternal GNAS allele.