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PubMed · 11600515

Galphas transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type 1b.

H Zheng·G Radeva·J A McCann·G N Hendy·C G Goodyer
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Abstract

Pseudohypoparathyroid type 1b patients are characterized by renal resistance to PTH in the absence of Albright's hereditary osteodystrophy or other endocrine abnormalities. Kindred studies have suggested that the cause of this resistance is a specific decrease in Galphas activity in renal proximal tubules due to paternal imprinting of Galphas. To test this, allelic expression of Galphas was analyzed in human fetal kidney cortex samples by RT-PCR assays. The results showed that, in contrast to the parent-specific expression of exon 1A and XLalphas (paternal) or NESP (maternal) mRNAs, Galphas transcripts are biallelically expressed in human kidney cortex. These data implicate abnormal imprinting of alternative regions within the GNAS1 locus as a more likely cause of pseudohypoparathyroid type 1b.

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GTP-Binding Protein alpha Subunits, GsGenomic ImprintingHeterotrimeric GTP-Binding ProteinsHumansKidney CortexPseudohypoparathyroidismRNA, MessengerJournal ArticleResearch Support, Non-U.S. Gov't

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H Zheng, G Radeva, J A McCann, G N Hendy, C G Goodyer. 2001. Galphas transcripts are biallelically expressed in the human kidney cortex: implications for pseudohypoparathyroidism type 1b.. https://doi.org/10.1210/jcem.86.10.7940

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PubMed2006

Different mutations within or upstream of the GNAS locus cause distinct forms of pseudohypoparathyroidism.

The term pseudohypoparathyroidism (PHP) refers to different disorders that are caused by mutations within GNAS or upstream of this complex genetic locus. GNAS gives rise to several different transcripts, including Gs alpha (alpha-subunit of the heterotrimeric stimulatory G protein), XL alpha s (extra-large variant of Gs alpha), and several additional sense and antisense transcripts. The complexity of the GNAS locus is furthermore reflected by a parent-specific methylation pattern of most of its different promoters. PHP can be divided into two major groups, PHP type Ia (PHP-Ia) and PHP type Ib (PHP-Ib). PHP-Ia is caused by heterozygous mutations affecting one of the 13 GNAS exons encoding Gs alpha. In contrast, PHP-Ib is caused by heterozygous deletions within STX16, the gene encoding syntaxin 16, which is located more than 220 kb upstream of GNAS, or by deletions within GNAS involving exon NESP55 and two of the antisense exons. In either form of PHP, hormonal resistance develops only after maternal inheritance of the mutation, while paternal inheritance of the same molecular defect is not associated with endocrine abnormalities. In most familial cases of PHP-Ib, there is a loss of exon A/B methylation combined with active A/B transcription from both parental alleles, which leads to suppression of Gs alpha transcription in the proximal renal tubules and, therefore, PTH resistance.

GTP-Binding Protein alpha Subunits, Gs↗