Biallelic Expression of the Gsα Gene in Human Bone and Adipose Tissue

Abstract

Mutations of the Gsalpha gene inherited from the mother lead to pseudohypoparathyroidism (PHP) type Ia (PHP Ia), in which Albright's hereditary osteodistrophy is associated to resistance to the action of different hormones, whereas the same mutations inherited from the father lead to isolated Albright's hereditary osteodistrophy [pseudo-PHP (PPHP)]. Accordingly, it has been suggested that Gsalpha is under tissue-specific imprinting control, and recent studies provided evidence for a predominant maternal origin of Gsalpha transcripts in different endocrine organs involved in the PHP Ia phenotype. To establish whether Gsalpha is imprinted also in tissues that are site of alteration both in PHP Ia and PPHP, we selected 20 bone and 10 adipose tissue samples, which were heterozygous for a known polymorphism in exon 5. Expression from both parental alleles was evaluated by RT-PCR and enzymatic digestion of the resulting fragments. By this approach, the great majority of the samples analyzed showed an equal expression of the two alleles. Our results provide evidence for the absence of Gsalpha imprinting in human bone and fat and suggest that the clinical finding of osteodystrophy and obesity in PHP Ia and PPHP patients despite the presence of a normal Gsalpha allele is likely due to Gsalpha haploinsufficiency in these tissues.

Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib

“…Our ΔNesp55 m /Gnasxl m+/p− mice demonstrated a normal calcemic response to PTH administration, indicating that the actions of PTH on bone are not impaired, as is also true in patients with PHP-Ib (48). This result likely reflects the absence of paternal Gαs silencing in this tissue (13).…”

“…The most downstream alternative first exon is Gαs exon 1, which generates transcripts encoding the ubiquitously expressed Gαs (6). The Gαs promoter resides within a nonmethylated CpG island, but despite the absence of differential methylation at its promoter, Gαs shows predominantly maternal expression in some tissues, including pituitary, thyroid, renal proximal tubules, and gonads (7-10); Gαs expression is biallelic in most other tissues (11)(12)(13). The furthest upstream alternative promoter generates transcripts that encode the neuroendocrine-specific protein of 55 kDa (NESP55; mouse Nesp55), a chromogranin-like protein, the coding sequence of which is located within a specific upstream exon; Gαs exons 2-13 reside within the 3′ untranslated region of NESP55 transcripts (14).…”

Dominance and gene dosage balance in health and disease: why levels matter!

“…In contrast, a mutation of the paternal allele results in isolated AHO. In sum, the AHO phenotype seems to arise from plain Gs(α) haploinsufficiency [45], while multihormone resistance in patients with maternal mutations is explained by the tissue-specific imprinting of the gene (and the silencing of the paternal allele in hormone target tissues) [43].…”

Studies of the regulation and function of the Gsα gene Gnas using gene targeting technology

“…These findings have been refuted by studies in adult G s α-specific knockout models in which G s α levels were reduced to a similar extent in WAT from maternal and paternal heterozygotes (Germain-Lee et al, 2005) and with only a small difference in G s α BAT expression between maternal and paternal heterozygotes (M. Chen et al, 2005a). One study also showed no evidence for G s α imprinting in human WAT (Mantovani et al, 2004). We suspect that the differential G s α expression observed in E2 m−/+ and E2 +/p− mice may result from secondary changes in G s α expression resulting from different levels of metabolic activity in adipose tissues of these mice (S. Yu et al, 2000) rather than imprinting.…”