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      GNAS Locus and Pseudohypoparathyroidism

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          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.

          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.

            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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              Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly.

              Approximately 40% of growth hormone-secreting pituitary adenomas have somatic mutations in the GNAS1 gene (the so-called gsp oncogene). These mutations at codon 201 or codon 227 constitutively activate the alpha subunit of the adenylate cyclase-stimulating G protein G(s). GNAS1 is subject to a complex pattern of genomic imprinting, its various promoters directing the production of maternally, paternally, and biallelically derived gene products. Transcripts encoding G(s)alpha are biallelically derived in most human tissues. Despite this, we show here that in 21 out of 22 gsp-positive somatotroph adenomas, the mutation had occurred on the maternal allele. To investigate the reason for this allelic bias, we also analyzed GNAS1 imprinting in the normal adult pituitary and found that G(s)alpha is monoallelically expressed from the maternal allele in this tissue. We further show that this monoallelic expression of G(s)alpha is frequently relaxed in somatotroph tumors, both in those that have gsp mutations and in those that do not. These findings imply a possible role for loss of G(s)alpha imprinting during pituitary somatotroph tumorigenesis and also suggest that G(s)alpha imprinting is regulated separately from that of the other GNAS1 products, NESP55 and XLalphas, imprinting of which is retained in these tumors.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                April 2005
                06 April 2005
                : 63
                : 2
                : 65-74
                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
                83895 Horm Res 2005;63:65–74
                © 2005 S. Karger AG, Basel

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