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Pseudohypoparathyreoidismus und epigenetische Veränderungen des GNAS-Genlocus

Pseudohypoparathyroidism and epigenetic alterations of the GNAS gene locus

Zusammenfassung

Die Bezeichnung Pseudohypoparathyreoidismus (PHP) beschreibt eine heterogene Gruppe von Erkrankungen, die durch eine Endorganresistenz gegenüber Parathormon (PTH) gekennzeichnet sind. Sie werden durch eine Defizienz der α-Untereinheit stimulierender G-Proteine (Gsα) verursacht. Gsα ist essenziell für die Signalvermittlung durch extrazelluläre Liganden über mehr als 1000 verschiedene G-Protein-gekoppelte Rezeptoren in das Zellinnere. Durch eine gewebespezifische Prägung verursachen maternale, autosomal-dominant vererbte Mutationen in dem für Gsα kodierenden GNAS-Genlocus PTH-Resistenz und klinische Zeichen der hereditären Albright-Osteodystrophie (AHO), einschließlich Brachymetakarpie, Kleinwuchs, subkutaner Ossifikationen und mentaler Retardierung (PHP-Typ Ia). Paternal vererbte GNAS-Mutationen führen zu selektiven AHO-Zeichen ohne Parathormonresistenz (Pseudo-PHP). Der PHP-Typ Ib, bei dem eine isolierte PTH-Resistenz vorliegt, wird durch heterozygote, maternal vererbte Deletionen stromaufwärts vom oder innerhalb des GNAS-Locus hervorgerufen, die durch eine Störung des Imprintingmusters eine gewebespezifische Stilllegung der Gsα-Expression hervorrufen. Diese Patienten zeigen in der Regel keine Zeichen der AHO. In der vorliegenden Arbeit wird ein Überblick über die Rolle epigenetischer Faktoren bei der Ätiopathogenese verschiedener PHP-Formen gegeben.

Abstract

The term pseudohypoparathyroidism (PHP) describes a heterogeneous group of related disorders characterized by end-organ resistance to parathyroid hormone (PTH). PHP is caused by deficiency of the α-subunit of stimulatory G proteins (Gsα), which is crucial for signal transduction of more than 1000 G protein-coupled receptors into the cell. PHP type Ia is caused by heterozygous, maternally inherited inactivating mutations involving those exons of the GNAS locus that encode Gsα. In addition, PHP Ia and Ic patients present with features of Albright hereditary osteodystrophy (AHO), which includes round face, short stature, brachymetacarpia, ectopic ossification, and mental retardation. Paternally inherited GNAS mutations lead to pseudo-PHP and are characterized by only some features of AHO in the absence of hormone resistance. PHP type Ib is caused by heterozygous, maternally inherited deletions up-stream of or within the GNAS locus that are associated with the loss of methylation at one or more maternally methylated regions within GNAS . Typically, these patients lack AHO features. This article provides an overview of the role of epigenetic factors for different PHP subtypes.

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung(en) hin: Die Autoren haben finanzielle Unterstützung vom BMBF unter dem Kennzeichen GMG 01GM0315 sowie von der Fa. Novo Nordisk erhalten.

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Correspondence to S. Thiele.

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Thiele, S., Hiort, O. Pseudohypoparathyreoidismus und epigenetische Veränderungen des GNAS-Genlocus. medgen 22, 419–423 (2010). https://doi.org/10.1007/s11825-010-0249-5

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Schlüsselwörter

  • Pseudohypoparathyreoidismus
  • Hereditäre Albright-Osteodystrophie
  • Humanes Protein des komplexen GNAS-Genlocus
  • Genetisches Imprinting
  • DNA-Methylierung

Keywords

  • Pseudohypoparathyroidism
  • Albright hereditary osteodystrophy
  • GNAS complex locus protein, human
  • Genomic imprinting
  • DNA methylation