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Pseudohypoparathyroidism

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Metabolic Bone Diseases

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Abstract

Pseudohypoparathyroidism is a rare disorder caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3. This locus is capable of undergoing parent-specific methylation changes at several sites. GNAS encodes the alpha subunit of the stimulatory G protein (Gsα) and its several splice variants. Pseudohypoparathyroidism type 1a is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1–13. Because paternal Gsα is not significantly expressed in the proximal renal tubule, thyroid, or pituitary, there is little or no normal Gsα protein in the presence of the maternal GNAS mutations, resulting in resistance to parathyroid hormone and consequent hyperparathyroidism, hypocalcemia, and hyperphosphatemia. Patients with pseudohypoparathyroidism type 1a have Albright’s hereditary osteodystrophy (AHO), with short stature, obesity, and shortened fourth and fifth metacarpal and metatarsal bones. When the same heterozygous inactivating mutations are present on the paternal GNAS allele, patients develop pseudopseudohypoparathyroidism, with features of AHO but without associated hyperparathyroidism, hypocalcemia, and hyperphosphatemia. Autosomal dominant pseudohypoparathyroidism type 1b is caused by heterozygous maternal deletion within GNAS or STX16, which are associated with loss of methylation at exon A/B alone or at all maternally methylated GNAS exons. Loss of methylation at exon A/B and the resulting biallelic expression of A/B transcripts reduce Gsα expression, leading to hormone resistance. Pseudohypoparathyroidism type 2 is thought to result from normal PTH/PTH-rp receptor-Gsα-adenylyl cyclase complex function but reduced action of the generated cAMP on downstream intracellular targets, such as sodium-phosphate cotransporters that mediate renal tubular phosphate reabsorption.

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  1. Mayo Clinic, Rochester, MN, USA

    Bart L. Clarke

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  1. Division of Endocrinology and Metabolism, Loyola University Medical Center, Maywood, IL, USA

    Pauline M. Camacho

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Clarke, B.L. (2019). Pseudohypoparathyroidism. In: Camacho, P. (eds) Metabolic Bone Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-03694-2_6

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  • DOI: https://doi.org/10.1007/978-3-030-03694-2_6

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