Gene Underlying Food-Dependent Cushing's Syndrome Identified

By Marilynn Larkin

October 28, 2021

NEW YORK (Reuters Health) - Mutations in the KDM1A gene are responsible for food-dependent Cushing's syndrome, a rare disease caused by the abnormal expression of GIP (glucose-dependent insulinotropic peptide) receptors in both adrenal glands.

This form of the syndrome is called GIP-dependent primary bilateral macronodular adrenal hyperplasia (PBMAH).

"We are doing more work in this area, since more than 70% of cases of PBMAH remain unexplained genetically," Dr. Isabelle Bourdeau of the University of Montreal and the CHUM Research Centre told Reuters Health by email. "We believe that more genes are involved and remain to be discovered."

"It is too early now to modify current clinical treatment," she acknowledged. "However, a better understanding of the genetic mechanisms involved in the development of PBMAH will open new, unsuspected avenues for treatment. Moreover, it enlarges the spectrum of diseases that may be associated with PBMAH, although this remains to be explored."

As reported in The Lancet Diabetes and Endocrinology, Dr. Bourdeau and colleagues analyzed data from 17 patients (median age, 43.3; 88% women) with GIP-dependent PBMAH with Cushing's syndrome. They collected blood and adrenal samples from those who had undergone unilateral or bilateral adrenalectomy for the condition.

Control samples came from patients with PBMAH who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production, and those with GIP-dependent unilateral adrenocortical adenomas.

Genomic analyses identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. A recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions also was identified.

By contrast, none of the 29 patients in the control groups had KDM1A germline or somatic alterations.

Genetic inactivation of both KDM1A alleles led to the loss of KDM1A expression in adrenal lesions. A global gene expression analysis showed GIP receptor upregulation with a log 2-fold change of 7.9, and differential regulation of several other G protein-coupled receptors in GIP-dependent PBMAH samples compared with controls.

In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells.

The authors state, "We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumor suppressor gene model of tumorigenesis. Genetic testing and counseling should be offered to these patients and their relatives."

Dr. Gary Hammer, Director - Endocrine Oncology at the University of Michigan Rogel Cancer Center in Ann Arbor, called the paper, "very important."

"This is the first demonstration of a molecular mechanism underlying aberrant receptor regulation in PBMAH," he said. "This finding will allow genetic screening for early detection of familial cases and possibly eventually personalized medical therapy."

"As KDM1A (lysine demethylase 1A) has previously been found in cases of multiple myeloma, myelodysplasia and other malignancies," he added, "it was intriguing to find associations with these malignancies in some of the affected cases."

SOURCE: The Lancet Diabetes and Endocrinology, online October 13, 2021.