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Review
. 2023 Dec 12;72(1):e230104.
doi: 10.1530/JME-23-0104. Print 2024 Jan 1.

Pseudohypoparathyroidism: complex disease variants with unfortunate names

Harald Jüppner  1
Affiliations
Review

Pseudohypoparathyroidism: complex disease variants with unfortunate names

Harald Jüppner. J Mol Endocrinol. .

Abstract

Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsα-coupled receptors.

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

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Conflict of interest statement

There is no conflict of interest.

Figures

Figure 1:
Figure 1:. Organization of the GNAS locus and the impact of Gsα mutations on either the maternal or the paternal allele.
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 biallelically expressed in most tissues red arrows, maternal; blue arrows, paternal), except for few tissues like renal proximal tubule, thyroid, pituitary, brown adipose tissue, various nuclei in the brain, and possibly other cells or tissues where paternal Gsα expression is partially or completely silenced through yet undefined mechanisms (light grey stippled arrow that is circled in red). The GNAS locus gives rise to at least five other transcripts, including the antisense transcript (AS), the NESP transcript encoding a neuroendocrine secretory protein (NESP), as well as the XL transcript encoding an extra-large form of Gsα, named XLαs, an exon H-derived transcript of unknown significance, 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 from the paternal allele. The NESP promoter is paternally methylated and active exclusively on the maternal allele. The NESP, XL and A/B transcripts, as well as the mRNA derived from exon H, are derived from their own unique first exons that splice onto GNAS exons 2–13. Immediately centromeric of the XL promoter resides the promoter for the antisense transcript AS. Maternal and paternal GNAS-derived mRNAs are shown above and below the gene structure, respectively. Boxes indicate exons and splicing patterns that are represented by broken/angled lines. Bent arrows indicate promoter start sites and direction of transcription. Red (maternal) or blue (paternal) asterisks indicate sites of differentially methylated regions (DMRs) in the maternal (XL, A/B, and AS) and the paternal (NESP) promoter regions.
Figure 2:
Figure 2:. Genetic causes of autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B) and associated GNAS methylation changes.
AD-PHP1B due to maternal deletions upstream of the Gsα-encoding exons that are associated with loss-of-methylation at one or more DMRs. Maternal deletions involving STX16 or NESP (green or black brackets) lead to loss-of-methylation at the A/B DMR alone. The same epigenetic GNAS changes that are restricted to the A/B DMR can also be due to a large genomic inversion (orange), different duplications (purple brackets) involving the maternal allele, and two retrotransposons (dark red arrow heads). 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 deletion of exon NESP (red brackets) result in loss-of-methylation at the three 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. Left panel: methylation of individual GNAS DMRs is indicated, maternal (left) and paternal (right); +, methylated; -, non-methylated; 0, region is deleted.
Figure 3:
Figure 3:. Establishment of methylation at GNAS exon A/B during oogenesis is disrupted by different maternal STX16/GNAS mutations thereby causing AD-PHP1B.
After erasure of the epigenetic modifications at all GNAS DMRs in primordial germ cells, methylation imprints (*) at exons A/B, XL, and AS are established before meiosis I during late oogenesis, which allows maintenance of Gsα transcription (red arrow). While NESP transcription (orange arrow) is required during oogenesis for establishing maternal methylation imprints at the exon A/B DMR, it is unknown whether STX16 expression (blue arrow) enhances NESP transcripts in maturing oocytes as it does in human embryonic stem (hES) cells. In the latter cells, STX16 deletions introduced into the maternal allele impair STX16 transcription (stippled purple arrow) thereby reducing NESP transcription (stippled black arrow) and exon A/B methylation, consequently limiting Gsα expression. These data are consistent with studies in mice that were engineered to comprise a polyadenylation signal down-stream of exon NESP and had provided evidence for the conclusion that lack of a nascent, NESP-derived transcript can prevent methylation at exon 1A (equivalent of the human exon A/B) thereby facilitating 1A transcription and reducing Gsα expression. Several mutations within the maternal STX16/GNAS locus cause AD-PHP1B variants that are associated with loss-of-methylation restricted to the exon A/B DMR. These include maternal deletions involving STX16 (purple cross) or exon NESP (black cross) but not any of the AS exons; both are predicted to lead to a lack of nascent NESP transcripts. Likewise, two different retrotransposons (dark red arrow), which introduce repetitive DNA sequences, several polyadenylation signals, and poly-adenine stretches into a region just telomeric of exon XL are likely to impair nascent NESP RNA. The resulting lack of methylation at the maternal A/B DMR and consequently active transcription from this exon (red arrow) reduces Gsα mRNA derived from this GNAS allele (pink stippled arrow).
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