Abstract
Congenital idiopathic megaesophagus (CIM) is a gastrointestinal (GI) motility disorder of dogs in which reduced peristaltic activity and dilation of the esophagus prevent the normal transport of food into the stomach. Affected puppies regurgitate meals and water, fail to thrive, and experience complications such as aspiration pneumonia that may necessitate euthanasia. The German shepherd dog (GSD) has the highest disease incidence, indicative of a genetic predisposition. Here, we discover that male GSDs are twice as likely to be affected as females and show that the sex bias is independent of body size. We propose that female endogenous factors (e.g., estrogen) are protective via their role in promoting relaxation of the sphincter between the esophagus and stomach, facilitating food passage. A genome-wide association study for CIM revealed an association on canine chromosome 12 (P-val = 3.12x10-13), with the lead SNPs located upstream or within Melanin-Concentrating Hormone Receptor 2 (MCHR2), a compelling positional candidate gene having a role in appetite, weight, and GI motility. Within the first intron of MCHR2, we identified a 33 bp variable number tandem repeat (VNTR) containing a consensus binding sequence for the T-box family of transcription factors. Across dogs and wolves, the major allele includes two copies of the repeat, whereas the predominant alleles in GSDs have one or three copies. The single-copy allele is strongly associated with CIM (P-val = 1.32x10-17), with homozygosity for this allele posing the most significant risk. Our findings suggest that the number of T-box protein binding motifs may correlate with MCHR2 expression and that an imbalance of melanin-concentrating hormone plays a role in CIM. We describe herein the first genetic factors identified in CIM: sex and a major locus on chromosome 12, which together predict disease state in the GSD with greater than 75% accuracy.
Highlights
Esophageal motility is an integrated neuromuscular process that, when dysregulated, causes an array of digestive disturbances [1]
We discovered that male German shepherd dog (GSD) are affected at a ratio of almost 2-to-1 over females, suggesting a protective biological advantage in females
In a genome-wide scan, we identified an association with congenital idiopathic megaesophagus (CIM) on chromosome 12 and, within this region, a repetitive sequence in Melanin-Concentrating Hormone Receptor 2 (MCHR2)
Summary
Esophageal motility is an integrated neuromuscular process that, when dysregulated, causes an array of digestive disturbances [1]. The most recognized and studied esophageal dysmotility is achalasia [4], characterized by constriction of the LES and aperistalsis, causing difficulty swallowing, coughing, chest pain, and regurgitation [5,6]. The most common esophageal dysmotility in dogs is congenital idiopathic megaesophagus (CIM) [7]. While gravity aids motility of the vertical human esophagus, it does not facilitate food passage in the horizontally-oriented canine esophagus. CIM-affected dogs have ineffective peristalsis, which leads to food retention that stretches and dilates the esophagus [8]. Overt clinical signs include coughing and regurgitation, usually beginning upon weaning at around four weeks of age [3,9]. CIM encompasses a broad phenotypic spectrum ranging from subclinical cases that may only be detected via radiography to severe cases with regurgitation episodes several times a day [7,9]. Affected puppies fail to thrive and are at risk for aspiration pneumonia [11] and intussusception [12,13]
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