GPR101 – Acromegaly

GPR101, located on chromosome Xq26.3, encodes an orphan G-protein-coupled receptor highly expressed in the hypothalamus and pituitary somatotrophs. Dysregulation of GPR101 has emerged as a pathogenic driver in disorders of growth hormone (GH) excess. While Xq26.3 microduplications encompassing GPR101 underlie X-linked acrogigantism in pediatric cases, recurrent somatic variants in GPR101 have been implicated in adult acromegaly. The distinction between germline duplication and somatic mutation highlights the gene's pleiotropic role in somatotroph tumorigenesis. Here, we summarize the genetic and functional evidence linking GPR101 to acromegaly. This evaluation supports routine molecular analysis of GPR101 in GH-secreting pituitary adenomas.

The first demonstration of GPR101 involvement in adult acromegaly came from sequencing of 248 sporadic cases, revealing the recurrent somatic c.924G>T (p.Glu308Asp) variant in 11 patients (4.4%) (PMID:25470569). No familial segregation was observed, consistent with a somatic mosaic pattern. Subsequent multicentric screening of 215 Italian acromegaly patients failed to detect germline p.Glu308Asp, reinforcing its somatic nature (PMID:26815903). Combined, these studies identify 11 unrelated probands harbouring somatic p.Glu308Asp, with no additional pathogenic variants reported. Segregation analysis remains limited by the absence of heritable transmission. Overall, the recurrent nature of p.Glu308Asp across independent cohorts underpins a strong gene–disease relationship.

In addition to p.Glu308Asp, Xq26.3 microduplications confined to GPR101 have been characterized in 12 patients with early-onset growth hormone excess (PMID:27245663). However, large-scale analyses of germline GPR101 coding regions in acromegaly have not identified missense, truncating, or splice variants beyond p.Glu308Asp. No structural or deep-intronic variants have been associated. The GPR101 variant spectrum in acromegaly is thus dominated by p.Glu308Asp, a gain-of-function allele arising somatically in tumor cells. This narrow spectrum supports focused molecular testing strategies.

Functional characterization of p.Glu308Asp via transfection into rat GH3 somatotroph cells demonstrated increased GH secretion and enhanced cellular proliferation, indicative of a gain-of-function mechanism recapitulating the human phenotype (PMID:25470569). The variant stimulates cAMP signaling pathways consistent with G-protein activation, mirroring the pathophysiology of somatotroph hyperplasia. No constitutive activity or dysregulated expression was documented for other GPR101 variants. These concordant in vitro findings provide moderate experimental evidence supporting the clinical association.

Multicentric screening for germline p.Glu308Asp in 215 patients yielded no positive cases, underscoring the variant's somatic restrictedness and limiting its utility for hereditary risk assessment (PMID:26815903). Similarly, broad sequencing of GPR101 in isolated GH deficiency cohorts failed to implicate loss-of-function alleles in GH regulation (PMID:26797872). These negative findings delimit the role of GPR101 to GH excess disorders rather than GH deficiency or corticotropinomas.

Targeted molecular testing of GPR101 for c.924G>T (p.Glu308Asp) in resected pituitary adenomas can confirm the genetic basis of sporadic acromegaly, potentially guiding personalized therapeutic approaches. Although no germline predisposition has been established, tumor genotyping may inform prognosis and new treatment strategies targeting GPR101-mediated signaling. Further studies are needed to define the prevalence of p.Glu308Asp in broader cohorts and explore pharmacological modulation. Key Take-home: Recurrent somatic GPR101 p.Glu308Asp is a validated genetic driver of acromegaly, offering a biomarker for diagnosis and a potential target for novel therapies.

References

• The New England Journal of Medicine • 2014 • Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. PMID:25470569
• Endocrine • 2016 • Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. PMID:26815903
• Acta neuropathologica communications • 2016 • Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. PMID:27245663
• Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme • 2016 • GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency. PMID:26797872

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