Pituitary-Dependent Hyperadrenocorticism (Cushing disease), CRHR1-related

Gene: CRHR1

Transmission: Uncharacterized

Mutation: Substitution, CRHR1 gene; c.289G>A, p.(Val97Met), exon4, chromosome 9.

Breed: Numerous breeds

Medical system: Endocrine

Age of onset of symptoms: Older dogs

Hyperadrenocorticism or Cushing disease is a common endocrine disorder seen in older dogs.  This is most often caused by a benign (adenoma) or a malignant (adenocarcinoma) tumor of the pituitary gland.  The main symptoms of hyperadrenocorticism include polyuria, polydipsia, polyphagia, muscle weakness, alopecia and abdominal extension, all due to the increased endogenous production of the glucocorticoid hormone cortisol by the adrenal gland as a result of aberrant hormone signaling by the pituitary tumor.

A candidate gene study of 50 poodles with diagnosed hyperadrenocorticism was performed to look for germline mutations within the CRHR1 gene as a possible cause for the disease.  CRHR1 is part of the hypothalamus-pituitary-adrenal hormone axis controlling the expression of the glucocorticoid cortisol by the adrenal gland.  It is the membrane bound pituitary cell receptor for CRH, the hypothalamic secreted releasing factor for the pituitary expression of ACTH.  An activating mutation was observed in one animal out of the 50 animals studied.  It is concluded that this mutation of the CRHR1 gene is not systematically present in dogs with Cushing’s syndrome.  Although this mutation is found at various frequencies within several dog breeds, its clinical significance has yet to be demonstrated.  The full genetic characterization of hyperadrenocorticism in the dog awaits additional studies.

References:

OMIA link: [0247-9615]

Langner K, Foster SF, Duff BC. (2025) Patient signalment and aetiology of hypercortisolism in Australian dogs with Cushing’s syndrome. Aust Vet J. [pm/39817411]

Hovious K, Fowler K, Beasly M, Pancotto TE. (2024) Cushing’s myopathy in dogs: Prevalence, clinical abnormalities, and response to treatment. Animals (Basel) 14:3109.  [pm/39518832]

Donner J, Freyer J, Davison S, et al. (2023) Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs.  PLoS Genet. 19(2):e1010651. [pubmed/36848397]

Fleeman L, Barrett R. (2023) Cushing syndrome and other causes of insulin resistance in dogs. Vet Clin North Am Small Anim Pract 53:711-730. [pm/36898861]

De-Marco V, Carvalho LR, Guzzo MF, et al. (2017) An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles.  Clinics (San Paulo) 72(9):575-581.  [pm/29069262]

Contributed by: Tommy Pepin and Félix Levine, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal.  (Translation DWS)