Affiliation:
1. Endocrine Unit, Department of Medicine and Pediatric Nephrology Unit, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Abstract
Abstract
Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright’s hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss of methylation at the A/B DMR alone or at all maternally methylated GNAS exons. Loss of methylation of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).
Funder
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney
Subject
Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism
Reference119 articles.
1. Minireview: GNAS: normal and abnormal functions;Weinstein;Endocrinology.,2004
2. Hypoparathyroidism and pseudohypoparathyroidism.;Levine,2005
3. Pseudohypoparathyroidism, Albright’s hereditary osteodystrophy, and progressive osseous heteroplasia: disorders caused by inactivating GNAS mutations.;Bastepe,2016
4. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement;Mantovani;Nat Rev Endocrinol.,2018
5. Paternally-inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia;Shore;New Engl J Med.,2002
Cited by
30 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献