Congenital idiopathic megaesophagus in the German shepherd dog is a sex-differentiated trait and is associated with an intronic variable number tandem repeat in Melanin-Concentrating Hormone Receptor 2.

Autor: Bell SM; Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America., Evans JM; Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.; Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America., Evans KM; The Seeing Eye Inc., Morristown, New Jersey, United States of America.; School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, United Kingdom., Tsai KL; Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America., Noorai RE; Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.; Clemson University Genomics and Bioinformatics Facility, Clemson University, Clemson, South Carolina, United States of America., Famula TR; Department of Animal Science, University of California, Davis, California, United States of America., Holle DM; The Seeing Eye Inc., Morristown, New Jersey, United States of America., Clark LA; Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2022 Mar 10; Vol. 18 (3), pp. e1010044. Date of Electronic Publication: 2022 Mar 10 (Print Publication: 2022).
DOI: 10.1371/journal.pgen.1010044
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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