In other species: crab-eating macaque , domestic cat , horse , pig , rabbit

Categories: Adipose tissue phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 164160 (gene) , 614962 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2016

Markers: Having conducted a case-control study involving 57 Labrador Retrievers affected with diabetes mellitus and 61 controls, Davison et al. (2017) reported that "There was no association between the presence of the POMC deletion mutation and DM in this population of Labrador retriever dogs", leading them to conclude that "This study adds to the existing scientific literature indicating that there is little evidence for a direct link between obesity and DM in dogs".

Sypniewski and Szydlowski (2023) analysed "41 canine orthologues of human genes linked to monogenic obesity in humans to identify genes associated with body weight in Labrador Retriever dogs. we analysed 11,520 variants from 50 dogs using a linear mixed model with sex, age, and sterilization as covariates and population structure as a random effect. ... Only the ADCY3 gene showed statistically significant association: TA>T deletion located at 17:19,222,459 in 1/20 intron (per allele effect of 5.56 kg, SE 0.018, p-value = 5.83 × 10-5, TA/TA: 11 dogs; TA/T: 32 dogs; T/T: 7 dogs)."

Molecular basis: Raffan et al. (2016) reported that "Sequencing of candidate genes for obesity in Labrador retriever dogs identified a 14 bp deletion in pro-opiomelanocortin (POMC) with an allele frequency of 12%. The deletion disrupts the β-MSH and β-endorphin coding sequences and is associated with body weight (per allele effect of 0.33 SD), adiposity, and greater food motivation. Among other dog breeds, the deletion was only found in the closely related flat-coat retriever (FCR), where it is similarly associated with body weight and food motivation"

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Obesity is a common condition that affects a large percentage of our companion animals (Raffan et al., 2016). Though a high calory diet and a lack of exercise may be at the base, a genetic component to obesity has been investigated (Raffan et al., 2016; Mankowska et al., 2017). A 14bp deletion in the proopiomelanocortin (POMC) gene was found in some Labrador retrievers and Flat-coated retrievers (Raffan et al., 2016). This mutation is predicted to disrupts the action of two peptides (β-MSH and β-endorphin), which are potent appetite and energy metabolism regulators. Due to a disrupted control of appetite, dogs with this mutation are more prone to overfeeding and hence gaining weight and adiposity (Raffan et al., 2016). An increased incidence of this mutation has been reported in assistance dogs, suggesting that selection of food-driven dogs for better trainability purposes inadvertently lead to the selection for this mutation . This mutation has not yet been identified in other breeds and doesn’t seem to have any correlation with diabetes mellitus to date (Davison et al., 2017).

IT thanks DVM student Martina Zanin, who provided the basis of this contribution in May 2023.

Prevalence: Intriguingly, Raffan et al. (2016) reported that the frequency of the POMC deletion was 45% "in a group of 81 Labrador retrievers used as assistance dog breeding stock" compared with a frequency of around 12% in random samples of Labrador Retrievers. As the authors explain, "Temperament and ‘‘trainability’’ are the main drivers for selection of assistance dogs, and ‘‘positive reinforcement’’ with food reward is a mainstay of puppy training. We therefore hypothesize that dogs carrying the POMC deletion may be more likely to be selected as assistance dogs. The fact that the allelic frequency at this locus is significantly out of Hardy-Weinberg equilibrium in assistance dog breeding stock could be seen as support for the notion that selection has occurred at this locus."

Breeds: Flat-Coated Retriever (Dog) (VBO_0200528), Labrador Retriever (Dog) (VBO_0200800).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated genes: