Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 615962 (trait) , 138040 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0014421: glucocorticoid resistance

Mendelian trait/disorder: yes

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: also called Chrousos syndrome

Molecular basis: Costa et al. (2015) sequenced the coding regions of the NR3C1 gene in 97 dogs from different breeds to identify variants that may explain individual variation in response to corticosteroid therapy. "A total of six single nucleotide polymorphisms (SNPs) were identified including four synonymous SNPs and two nonsynonymous SNPs (c.811A>T and c.2111T>C)." Both missense variants were predicted to be to be ‘probably damaging’. Yamanaka et al. (2019) "discovered a mutant GR [glucocorticoid receptor, now named NR3C1] in a dog suspected to have iatrogenic Cushing syndrome. The mutant GR had [69] extra nucleotides between exons 6 and 7, resulting in a truncated form of GR that was 98 amino acids shorter than the wild-type dog GR. The truncated GR exhibited very low reactivity to prednisolone, irrespective of concentration." The authors showed that the "truncated form showed the very less sensitivity to glucocorticoid in vitro, unfortunately, we could not elucidate its clinical significance."

Clinical features: Yamanaka et al. (2019) reported a single affected '6-year-old spayed, mixed-breed dog ... . The dog was tentatively diagnosed with pemphigus foliaceus at a private hospital 9 months previously. The dog had been treated with prednisolone ... for approximately 3 months. After the dog was started on the medication, polyuria, polydipsia, and abdominal distension were observed. The pemphigus foliaceus was neither ameliorated nor aggravated. After prednisolone withdrawal, calcinosis cutis was observed on the dorsal skin. Two months later ... the adverse reaction due to glucocorticoid therapy had already disappeared, except for extremely severe calcinosis cutis over the entire dorsal skin ... ." The authors diagnosed glucocorticoid resistance in this dog with iatrogenic Cushing syndrome.

Breed: Mixed Breed (Dog) (VBO_0200902).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: