Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome - Physiologie et physiopathologie endocriniennes - UMR-S 1185 Access content directly
Journal Articles JCI Insight Year : 2017

Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome

Anne Lecoq
  • Function : Author
Antoine Tosca
  • Function : Author
Mirella Hage
  • Function : Author
Patrick Hanna
  • Function : Author
Clovis Adam
  • Function : Author
Vanessa Benhamo
  • Function : Author
Antoine Tachdjian
  • Function : Author
Isabelle Bourdeau
  • Function : Author
Dominique Maiter
  • Function : Author
Wouter de Herder

Abstract

GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing's syndrome and one patient with GIP-dependent aldosteronism. GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had a 19q duplication only. We demonstrated that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in adenoma cells. Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing's syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations.
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hal-01904330 , version 1 (08-12-2023)

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Anne Lecoq, Constantine A. Stratakis, Say Viengchareun, Ronan Chaligné, Lucie Tosca, et al.. Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome. JCI Insight, 2017, 2 (18), ⟨10.1172/jci.insight.92184⟩. ⟨hal-01904330⟩
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