A large deletion on CFA28 omitting ACSL5 gene is associated with intestinal lipid malabsorption in the Australian Kelpie dog breed

Mitchell J. O’Brien,Mandy Sansom,Tracy Chew,Niek J. Beijerink,Sarah W. Thornton,Claire M. Wade

doi:10.1038/s41598-020-75243-x

Mitchell J. O’Brien, Mandy Sansom + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-75243-x

Copy DOI

Journal: Scientific Reports	Publication Date: Oct 26, 2020
Citations: 6	License type: open-access

Affiliation: University of Sydney

Abstract

Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients. In an Australian Kelpie breeding population, 17 puppies presented with intestinal lipid malabsorption. Juvenile dogs exhibited stunted postnatal growth, steatorrhea, abdominal distension and a wiry coat. Using genome-wide association analysis, an associated locus on CFA28 (Praw = 2.87E−06) was discovered and validated in a closely related population (Praw = 1.75E−45). A 103.3 kb deletion NC_006610.3CFA28:g.23380074_23483377del, containing genes Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) and Zinc Finger DHHC-Type Containing 6 (ZDHHC6), was characterised using whole transcriptomic data. Whole transcriptomic sequencing revealed no expression of ACSL5 and disrupted splicing of ZDHHC6 in jejunal tissue of affected Kelpies. The ACSL5 gene plays a key role in long chain fatty acid absorption, a phenotype similar to that of our affected Kelpies has been observed in a knockout mouse model. A PCR-based diagnostic test was developed and confirmed fully penetrant autosomal recessive mode of inheritance. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for intestinal lipid malabsorption in the Australian Kelpie.

Highlights

Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients
Inborn errors of metabolism (IEM) are genetic disorders resulting from defects in biochemical pathways that can have a profound effect on an animal’s overall health[22,23]
Reported metabolic disorders clinically similar to intestinal lipid malabsorption are hereditary selective ileal cobalamin malabsorption and exocrine pancreatic insufficiency. Both are IEM that present with failure to thrive and persistent diarrhea[11,25,26], the Australian Kelpie (AK) presents earlier, show no signs of lethargy and have clear evidence of fat in faeces

Summary

Introduction

Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients. In an Australian Kelpie breeding population, 17 puppies presented with intestinal lipid malabsorption. The ACSL5 gene plays a key role in long chain fatty acid absorption, a phenotype similar to that of our affected Kelpies has been observed in a knockout mouse model. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for intestinal lipid malabsorption in the Australian Kelpie. Long chain fatty acids (LCFA) are the most abundant fats in mammals and play a key role in the canine (Canis lupus familiaris) diet. Thirteen homologous ACS genes that activate LCFA have been annotated in mammals and cluster in three different gene families: acylCoA synthetase long chain (ACSL), acyl-CoA synthetase bubblegum (ACSBG) and fatty acid transport proteins (FATP)[1,2,3].

Objectives

Methods

Results

Conclusion