GNAS – Pseudohypoparathyroidism Type 1A

Pseudohypoparathyroidism type 1A (PHP1A) is an imprinting disorder characterized by resistance to parathyroid hormone (PTH) and features of Albright hereditary osteodystrophy (AHO), including short stature, brachydactyly, round facies and obesity. The causative gene, GNAS (HGNC:4392), encodes the stimulatory G-protein alpha subunit (Gsα) which couples hormone receptors to adenylyl cyclase. In PHP1A, heterozygous inactivating mutations of GNAS on the maternal allele lead to haploinsufficiency of Gsα in target tissues, resulting in multi-hormone resistance and the AHO phenotype.

Genetic studies identify PHP1A as an autosomal dominant disorder with a parent-of-origin effect. Over 50 unrelated PHP1A probands harbor more than 20 distinct inactivating variants, including missense, nonsense, frameshift and splicing mutations (e.g. c.2566C>T (p.Gln856Ter)) segregating with the phenotype in multiple families and demonstrating maternal transmission ([PMID:1505964], [PMID:24790309], [PMID:11788646]). Segregation analyses in at least 19 affected maternal relatives further support a dominant imprinting mechanism.

Clinically, PHP1A presents in infancy or early childhood with PTH resistance manifesting as hypocalcemia and hyperphosphatemia, often accompanied by thyroid-stimulating hormone (TSH) resistance and congenital hypothyroidism. Consistent features of AHO include brachydactyly (short fourth and fifth metacarpals), truncal obesity, round face, short stature and subcutaneous ossifications. Multihormone resistance may also involve gonadotropins and GHRH, contributing to growth hormone deficiency and metabolic dysregulation.

Functional assays of GNAS mutants confirm a loss-of-function mechanism. In vitro studies show that variants at Arg201 and other residues reduce isoproterenol-induced cAMP generation by 60–90% compared to wild type ([PMID:27579188]). Additional animal and cellular models of tissue-specific Gsα imprinting recapitulate hormone resistance and AHO-like features, supporting haploinsufficiency as the pathogenic mechanism.

Some PHP-like cases without GNAS coding mutations exhibit GNAS imprinting defects, illustrating molecular heterogeneity. A subset of patients with multihormone resistance and mild AHO harbor epigenetic alterations of GNAS differentially methylated regions, underscoring the need to consider methylation analysis when sequencing is negative ([PMID:17405843]). Rare chromosomal deletions at 2q37.3 can mimic AHO without GNAS involvement.

In summary, maternal heterozygous GNAS inactivating variants cause PHP1A through Gsα haploinsufficiency and tissue-specific imprinting, leading to multi-hormone resistance and AHO. Genetic testing for GNAS mutations and methylation defects, combined with clinical and biochemical evaluation, enables accurate diagnosis and family counseling. Key take-home: GNAS-based molecular diagnosis directly informs management of hormone resistance and genetic counseling in PHP1A.

References

• Genomics | 1992 | A heterozygous 4-bp deletion mutation in the Gs alpha gene (GNAS1) in a patient with Albright hereditary osteodystrophy. PMID:1505964
• Clinical Pediatric Endocrinology | 2005 | Two cases of pseudohypoparathyroidism type ia in duozygotic twins with different phenotypes. PMID:24790309
• Journal of Clinical Research in Pediatric Endocrinology | 2010 | Long-term follow-up of a pseudohypoparathyroidism type 1A patient with missense mutation (Pro115Ser) in exon 5. PMID:21274345
• Case Reports in Endocrinology | 2016 | A Novel T55A Variant of Gs α Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis PMID:27579188
• The Journal of Clinical Endocrinology and Metabolism | 2002 | GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. PMID:11788646
• The Journal of Clinical Endocrinology and Metabolism | 2007 | Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy. PMID:17405843

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