CLINICS

Clinics (Sao Paulo). 2017 September; 72(9): 575-581.
doi:10.6061/clinics/2017(09)09

Copyright © 2017 CLINICS

An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles

Viviani De-Marco I II * , Luciani R. Carvalho I , Mariana F. Guzzo I , Paulo S.L. Oliveira III , Larissa G. Gomes I , Berenice B. Mendonca I *

Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, BR

Curso de Medicina Veterinaria, Universidade de Santo Amaro, Sao Paulo, SP, BR

Laboratorio Nacional de Biociencias – LNBio, Campinas, SP, BR

*Corresponding authors. E-mail: vivianidemarco@gmail.com / beremen@usp.br

received December 16, 2017; revised February 17, 2017; accepted May 16, 2017.

Abstract

OBJECTIVES:

Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism.

METHODS:

Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing.

RESULTS:

The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH.

CONCLUSION:

These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.

Keywords: Hyperadrenocorticism, CRHR1, Mutation, Cushing’s Disease, Dogs


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