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Updated: Feb 3, 2026

Mutagenesis and Analysis of Genetic Mutations in the GC-rich KISS1 Receptor Sequence Identified in Humans with Reproductive Disorders
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Hypermethylator Phenotype and Ectopic GIP Receptor in GNAS Mutation-Negative Somatotropinomas

Mirella Hage1,2,3, Ronan Chaligné4,5, Say Viengchareun1,2

  • 1Institut National de la Santé et de la Recherche Médicale, Le Kremlin Bicêtre, France.

The Journal of Clinical Endocrinology and Metabolism
|October 31, 2018
PubMed
Abstract

Insights

A new molecular subtype of somatotropinomas, causing acromegaly, is linked to ectopic glucose-dependent insulinotropic polypeptide receptor (GIPR) expression. This finding sheds light on gigantism and acromegaly pathogenesis beyond GNAS mutations.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • The molecular basis of somatotropinomas, leading to gigantism and acromegaly, is not fully understood beyond GNAS gene mutations.
  • A subset of acromegaly patients exhibits paradoxical growth hormone (GH) secretion after oral glucose intake.

Purpose of the Study:

  • To investigate alternative molecular drivers in somatotropinoma development.
  • To identify the cause of paradoxical GH secretion in response to oral glucose in acromegalic patients.

Main Methods:

  • Analysis of 41 somatotropinoma samples using array-comparative genomic hybridization, RNA/DNA fluorescence in situ hybridization, and RRBS DNA methylation analysis.
  • Focus on patients with paradoxical GH response to oral glucose.

Main Results:

  • Ectopic glucose-dependent insulinotropic polypeptide receptor (GIPR) expression was found in 32% of somatotropinomas, including all 10 patients with paradoxical GH response.
  • GIPR expression was associated with GNAS mutation negativity, GIPR gene microamplifications, and DNA methylation abnormalities, particularly hypermethylation in the GIPR gene body.
  • A distinct molecular subclass of somatotropinomas was identified, characterized by ectopic GIPR expression.

Conclusions:

  • Ectopic GIPR expression in somatotropinomas represents a distinct molecular subclass.
  • This ectopic expression, driven by transcriptional activation, microamplifications, and methylation changes, explains the paradoxical GH secretion observed in some acromegaly patients.
  • The findings expand the understanding of somatotropinoma pathogenesis beyond GNAS mutations.

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