GNAS  Locus and Pseudohypoparathyroidism

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Abstract

Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH). Patients with PHP-Ia often present with additional hormonal resistance and show characteristic physical features that are collectively termed Albright’s hereditary osteodystrophy (AHO). These features are also present in pseudopseudohypoparathyroidism (PPHP), but patients affected by this disorder do not show hormone resistance. PHP-Ib patients, on the other hand, present predominantly with renal PTH resistance and lack any features of AHO. Most of these PHP forms are caused by defects in GNAS (20q13.3), an imprinted gene locus with multiple transcriptional units. PHP-Ia and PPHP are caused by heterozygous inactivating mutations in those exons of GNAS encoding the α subunit of the stimulatory guanine nucleotide-binding protein (Gsα), and the autosomal dominant form of PHP-Ib (AD-PHP-Ib) is caused by heterozygous mutations disrupting a long-range imprinting control element of GNAS. Expressed nearly in all cells, Gsα plays essential roles in a multitude of physiological processes. Its expression in renal proximal tubules occurs predominantly from the maternal allele, and this tissue- and parent-specific imprinting of Gsα is an important determinant of hormone resistance in kindreds with PHP-Ia/PPHP and AD-PHP-Ib.

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The imprinted signaling protein XL alpha s is required for postnatal adaptation to feeding.

Emma Gordon, Antonius Plagge, Romina Boiani … (2004)

Genomic imprinting, by which maternal and paternal alleles of some genes have different levels of activity, has profound effects on growth and development of the mammalian fetus. The action of imprinted genes after birth, in particular while the infant is dependent on maternal provision of nutrients, is far less well understood. We disrupted a paternally expressed transcript at the Gnas locus, Gnasxl, which encodes the unusual Gs alpha isoform XL alpha s. Mice with mutations in Gnasxl have poor postnatal growth and survival and a spectrum of phenotypic effects that indicate that XL alpha s controls a number of key postnatal physiological adaptations, including suckling, blood glucose and energy homeostasis. Increased cAMP levels in brown adipose tissue of Gnasxl mutants and phenotypic comparison with Gnas mutants suggest that XL alpha s can antagonize Gs alpha-dependent signaling pathways. The opposing effects of maternally and paternally expressed products of the Gnas locus provide tangible molecular support for the parental-conflict hypothesis of imprinting.

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Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.

R. Gardner, Jaimo Ahn, F Kaplan … (2002)

Progressive osseous heteroplasia (POH), an autosomal dominant disorder, is characterized by extensive dermal ossification during childhood, followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue. Occasional reports of mild heterotopic ossification in Albright's hereditary osteodystrophy (AHO) and a recent report of two patients with AHO who had atypically extensive heterotopic ossification suggested a common genetic basis for the two disorders. AHO is caused by heterozygous inactivating mutations in the GNAS1 gene that result in decreased expression or function of the alpha subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase. We tested the hypothesis that GNAS1 mutations cause POH, using the polymerase chain reaction to amplify GNAS1 exons and exon-intron boundaries in 18 patients with sporadic or familial POH. Heterozygous inactivating GNAS1 mutations were identified in 13 of the 18 probands with POH. The defective allele in POH is inherited exclusively from fathers, a result consistent with a model of imprinting for GNAS1. Direct evidence that the same mutation can cause either POH or AHO was observed within a single family, in which the phenotype correlated with the parental origin of the mutant allele. Paternally inherited inactivating GNAS1 mutations cause POH. This finding extends the range of phenotypes derived from haplo insufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that Gsalpha is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

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Progressive osseous heteroplasia.

F Kaplan, Roy E. Shore (2000)

Progressive osseous heteroplasia (POH) is a recently described genetic disorder of mesenchymal differentiation characterized by dermal ossification during infancy and progressive heterotopic ossification of cutaneous, subcutaneous, and deep connective tissues during childhood. The disorder can be distinguished from fibrodysplasia ossificans progressiva (FOP) by the presence of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumorlike swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional patterns of heterotopic ossification, and the predominance of intramembranous rather than endochondral ossification. POH can be distinguished from Albright hereditary osteodystrophy (AHO) by the progression of heterotopic ossification from skin and subcutaneous tissue into skeletal muscle, the presence of normal endocrine function, and the absence of a distinctive habitus associated with AHO. Although the genetic basis of POH is unknown, inactivating mutations of the GNAS1 gene are associated with AHO. The report in this issue of the JBMR of 2 patients with combined features of POH and AHO--one with classic AHO, severe POH-like features, and reduced levels of Gsalpha protein and one with mild AHO, severe POH-like features, reduced levels of Gsalpha protein, and a mutation in GNAS1--suggests that classic POH also could be caused by GNAS1 mutations. This possibility is further supported by the identification of a patient with atypical but severe platelike osteoma cutis (POC) and a mutation in GNAS1, indicating that inactivating mutations in GNAS1 may lead to severe progressive heterotopic ossification of skeletal muscle and deep connective tissue independently of AHO characteristics. These observations suggest that POH may lie at one end of a clinical spectrum of ossification disorders mediated by abnormalities in GNAS1 expression and impaired activation of adenylyl cyclase. Analysis of patients with classic POH (with no AHO features) is necessary to determine whether the molecular basis of POH is caused by inactivating mutations in the GNAS1 gene.

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2005

Publication date (Print): April 2005

Publication date (Electronic): 06 April 2005

Volume: 63

Issue: 2

Pages: 65-74

Affiliations

^aEndocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, and ^bPediatric Nephrology, MassGeneral Hospital for Children, Massachusetts General Hospital, Harvard Medical School, Boston, Mass., USA

Article

Publisher ID: 83895 Other ID: Horm Res 2005;63:65–74

DOI: 10.1159/000083895

PubMed ID: 15711092

SO-VID: 17f3a833-549f-41cb-8017-332da8891512

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 21 July 2004

Date accepted : 19 August 2004

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Figures: 4, Tables: 1, References: 66, Pages: 10

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GNAS Locus and Pseudohypoparathyroidism

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Most cited references 45

The imprinted signaling protein XL alpha s is required for postnatal adaptation to feeding.

Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.

Progressive osseous heteroplasia.

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