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Review
. 2021 May 13;106(6):1541-1552.
doi: 10.1210/clinem/dgab060.

Molecular Definition of Pseudohypoparathyroidism Variants

Harald Jüppner  1
Affiliations
Review

Molecular Definition of Pseudohypoparathyroidism Variants

Harald Jüppner. J Clin Endocrinol Metab. .

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).

Keywords: GNAS; STX16; Gs-alpha; PTH; TSH; cAMP; calcium; epigenetics; parent-specific GNAS methylation; phosphate; pseudohypoparathyroidism.

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Figures

Figure 1.
Figure 1.
Organization of the GNAS locus. The GNAS complex gives rise to several imprinted sense and antisense transcripts. Gsα, the most abundant product derived from this locus, is encoded by exons 1-13. This transcript is mostly biallelically expressed, except for few tissues like renal proximal tubule, thyroid, pituitary, brown adipose tissue, gonads, and various nuclei in the brain where paternal Gsα expression is partially or completely silenced through yet undefined mechanisms. The GNAS locus gives rise to 4 other transcripts, including the antisense transcript (AS), the NESP transcript encoding the neuroendocrine secretory protein 55 (NESP55), as well as the transcript encoding an extra-large form of Gsα, named XLαs, and the A/B transcript (1A in mice) that may give rise to an amino-terminally truncated Gsα. Promoters for XL, A/B and AS transcripts are methylated on the maternal allele and thus transcribed exclusively from the paternal allele. The NESP promoter is paternally methylated and active exclusively on the maternal allele. The NESP, XLαs, and A/B transcripts are derived from unique first exons that splice onto GNAS exon 2-13. Immediately centromeric of the XL promoter lies the promoter for the antisense transcript AS. Mutations involving any of the thirteen GNAS exons encoding Gsα are associated with AHO (Albright’ hereditary osteodystrophy) with or without hormone resistance based on which parental allele is affected, namely pseudohypoparathyroidism 1A (PHP1A), if a mutation is present on the maternal allele (horizontal red bracket), or pseudopseudohypoparathyroidism (PPHP) and progressive osseus heteroplasia (POH), if a mutation is present on the paternal allele (horizontal blue bracket). Maternal and paternal GNAS-derived mRNAs are shown above and below the gene structure. Boxes indicate exons and splicing patterns are represented by broken/angled lines. Bent arrows indicate promoter start sites and direction of transcription. *Sites of differentially methylated regions (DMRs) on the maternal (XL, A/B, and AS) and the paternal (NESP) promoters.
Figure 2.
Figure 2.
Genetic causes of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B). AD-PHP1B due to maternal deletions upstream of the Gsα-coding region that are associated with loss of methylation at one or more DMRs. Maternal deletions of STX16 or NESP (green or black brackets) lead to loss of methylation specifically at the A/B DMR. The same epigenetic GNAS changes can also be due to a large genomic inversion (orange) or due to different duplications (purple brackets) involving the maternal allele. Deletion of AS exons 3-4 on the paternal allele (light blue bracket) leads to a partial loss of methylation at the paternal NESP DMR and a partial gain of methylation at the paternal A/B DMR. Maternal deletions that include AS exons 3-4 alone or in combination with exon NESP (red brackets) result in loss of methylation at all 3 maternal GNAS DMRs (A/B, XL, and AS). Boxes and connecting lines represent exons and introns, respectively. Arrows indicate direction of transcription. Brackets indicate deletions or duplications.
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