GNAS – Pseudohypoparathyroidism Type 1B

Pseudohypoparathyroidism type 1B (MONDO:0011301) is an imprinting disorder caused by maternal‐specific epigenetic defects at the GNAS locus (HGNC:4392). Affected individuals present with renal resistance to parathyroid hormone leading to hypocalcemia and hyperphosphatemia, without features of Albright hereditary osteodystrophy. Loss of methylation (LOM) at the exon A/B differentially methylated region (DMR), often accompanied by broader methylation defects of the XL and NESP DMRs, underlies the disease mechanism.

Familial cases are most often due to maternally inherited microdeletions in STX16 or NESP55 that disrupt imprinting, whereas sporadic cases arise from maternal 20q uniparental disomy or primary epimutations. In a study of 84 PHP1B subjects (including 27 familial and 26 sporadic cases), all showed exon A/B LOM, with 7 families harboring a recurrent 3 kb STX16 deletion and one kindred carrying a novel NESP deletion (PMID:34157100). Additional rare multilocus imprinting defects have been documented in multisyndromic imprinting disturbance cases.

Segregation analysis in familial PHP1B demonstrates maternal transmission with complete or reduced penetrance. Across kindreds, over 27 affected relatives segregate with defined deletions or duplications (PMID:34157100; PMID:35859320). Variant classes include STX16 deletions (3 kb), GNAS exon A/B duplications, and retrotransposon insertions upstream of exon A/B. Coding loss‐of‐function mutations in GNAS (e.g., c.2494_2497del (p.Asp832Ter)) illustrate that disruption of Gsα dosage recapitulates hormone resistance when maternally inherited.

Functional studies reveal reduced Gsα protein levels in patient platelets with corresponding decreases in receptor‐stimulated and cholera toxin–induced cAMP formation (e.g., exon XL and 1A demethylation in MEG‐01 cells leads to reduced Gsα expression) (PMID:12374764). Quantitative pyrosequencing confirms mosaic or complete DMR LOM consistent across tissues, supporting early postzygotic epimutations that escape uniparental disomy screens (PMID:29445425).

Mouse and cellular models show that maternal Gsα deficiency causes renal PTH resistance and multihormone signaling defects, whereas paternal mutations spare hormone responsiveness. Rescue of Gsα expression via demethylating agents in vitro normalizes cAMP responses, demonstrating the cis‐regulatory nature of the defect.

One Finnish cohort of 88 children with isolated severe obesity found no GNAS methylation changes or STX16 deletions, indicating that isolated obesity without PTH resistance does not warrant routine GNAS epigenetic testing (PMID:32318528).

In summary, PHP1B is a definitive GNAS imprinting disorder with strong genetic and functional concordance: over 80 patients including 27 familial probands demonstrate maternal imprinting defects, multigenerational segregation, and consistent Gsα deficiency. Diagnostic testing for DMR methylation and STX16/GNAS structural defects is clinically useful for early detection and management of hypocalcemia.

Key Take-home: GNAS imprinting analysis is critical for diagnosing PHP1B, guiding calcium/phosphate management and family counseling.

References

• Human molecular genetics • 2002 • Pseudohypoparathyroidism type Ib with disturbed imprinting in the GNAS1 cluster and Gsalpha deficiency in platelets. PMID:12374764
• The Journal of clinical endocrinology and metabolism • 2021 • High-throughput Molecular Analysis of Pseudohypoparathyroidism 1b Patients Reveals Novel Genetic and Epigenetic Defects. PMID:34157100
• Frontiers in pediatrics • 2020 • GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children. PMID:32318528

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