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A GNAS1 imprinting defect in pseudohypoparathyroidism type IB
J Liu1, D Litman, M J Rosenberg
1Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and. Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-1752, USA.
The Journal of Clinical Investigation
|November 9, 2000
Summary
Pseudohypoparathyroidism type IB (PHPIB) results from abnormal imprinting of the GNAS gene's exon 1A region. This epigenetic defect leads to impaired parathyroid hormone (PTH) signaling in the kidneys.
Area of Science:
- Endocrinology
- Genetics
- Epigenetics
Background:
- Pseudohypoparathyroidism type IB (PHPIB) presents as parathyroid hormone (PTH) resistance specifically in the kidneys.
- Genetic mapping of familial PHPIB points to chromosome 20q13, near the GNAS1 gene encoding the G(s)alpha protein.
- Normal G(s)alpha function in blood cells excludes mutations in the coding region, suggesting an epigenetic or imprinting defect.
Purpose of the Study:
- To investigate the underlying genetic and epigenetic mechanisms causing Pseudohypoparathyroidism type IB.
- To identify the specific molecular defect responsible for PTH resistance in PHPIB patients.
Main Methods:
- Analysis of GNAS1 gene imprinting patterns in renal proximal tubules.
- Methylation analysis of a region upstream of the G(s)alpha promoter.
- Transcriptional analysis of alternative GNAS1 transcripts (exon 1A).
Main Results:
- Identified a critical region upstream of the G(s)alpha promoter with altered methylation patterns in PHPIB patients.
- This region contains an alternative promoter and exon 1A, normally imprinted.
- PHPIB patients exhibit biallelic expression of exon 1A, indicating a loss of paternal-specific imprinting.
Conclusions:
- Loss of imprinting in the GNAS exon 1A region is the likely cause of Pseudohypoparathyroidism type IB.
- This epigenetic defect may lead to reduced G(s)alpha expression in renal proximal tubules, causing PTH resistance.
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