GNAS – Progressive Osseous Heteroplasia (POH)

Progressive osseous heteroplasia (POH) is a rare, autosomal dominant disorder characterized by progressive heterotopic ossification of the dermis, subcutaneous fat, and deep connective tissues. POH is caused by heterozygous, paternally inherited inactivating mutations in GNAS (HGNC:4392), which encodes the Gsα subunit of the stimulatory G protein. Due to imprinting at the GNAS locus, loss of function on the paternal allele abolishes Gsα-mediated cAMP signaling in nonosseous tissues, promoting ectopic bone formation (PMID:11784876).

Clinical Validity

Based on ClinGen criteria, the GNAS–POH association is classified as Strong. In a multi-center series of 18 probands with sporadic or familial POH, 13 carried heterozygous inactivating GNAS mutations inherited exclusively from fathers, with direct evidence of the same mutation causing Albright hereditary osteodystrophy in maternally inherited cases (PMID:11784876). Functional concordance and imprinting studies further support causality.

Genetic Evidence

Inheritance is autosomal dominant with paternal imprinting. Segregation analyses documented at least 1 affected relative with the mutant GNAS allele. Reports include at least 13 probands harboring diverse loss-of-function variants—nonsense, frameshift, splice and deep-intronic mutations—reaching the ClinGen genetic evidence cap. A recurrent example is c.2728C>T (p.Gln910Ter) (PMID:11784876).

Functional / Experimental Evidence

Mechanistically, GNAS loss-of-function leads to haploinsufficiency of Gsα and impairment of cAMP synthesis. A heterozygous 4-bp deletion in exon 7 yields ~50% reduction in GNAS mRNA and absent Gsα protein from the mutant allele in patient cells (PMID:1505964). In vitro, GNAS mutants fail to mediate receptor- or cholera toxin–stimulated cAMP accumulation in Gnas-null fibroblasts, mirroring human POH pathology (PMID:16484323).

Conflicting Evidence

Some patients with POH-like ossification and AHO features lack detectable GNAS mutations, implicating alternative epigenetic or yet-unknown molecular mechanisms in rare cases (PMID:25894639).

Integration & Clinical Utility

Collectively, the genetic, segregation, imprinting, and functional data establish a strong causal link between paternally inherited GNAS loss-of-function mutations and POH. Genetic testing for paternal GNAS mutations informs diagnosis, prognosis, and family counseling. While targeted therapies remain under investigation, recognition of the GNAS imprinting mechanism is critical for accurate interpretation of negative maternal inheritance studies.

Key Take-home: Paternally inherited, inactivating GNAS mutations cause progressive heterotopic ossification via Gsα haploinsufficiency; genetic testing expedites diagnosis and guides clinical management.

References

• The New England journal of medicine • 2002 • Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia PMID:11784876
• Genomics • 1992 • A heterozygous 4-bp deletion mutation in the Gs alpha gene (GNAS1) in a patient with Albright hereditary osteodystrophy PMID:1505964
• Endocrinology • 2006 • Coding GNAS mutations leading to hormone resistance impair in vitro agonist- and cholera toxin-induced adenosine cyclic 3',5'-monophosphate formation mediated by human XLalphas PMID:16484323
• Journal of pediatric endocrinology & metabolism • 2015 • Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophy PMID:25894639

Evidence Based Scoring (AI generated)