Investigation of Genetic Modifiers of Copper Toxicosis in Labrador Retrievers

Xiaoyan Wu,Elise R Den Boer,Isaäc J Nijman,Peter A J Leegwater,Hille Fieten,Frank G Van Steenbeek,Glen R Monroe,Manon Vos-Loohuis

doi:10.3390/life10110266

Xiaoyan Wu, Elise R Den Boer + Show 6 more

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https://doi.org/10.3390/life10110266

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Journal: Life	Publication Date: Oct 31, 2020
Citations: 12	License type: CC BY 4.0

Affiliation: Utrecht University, University Medical Center Utrecht

Abstract

Copper toxicosis is a complex genetic disorder in Labrador retrievers characterized by hepatic copper accumulation eventually leading to liver cirrhosis. The variation of hepatic copper levels in Labrador retrievers has been partly explained by mutations in ATP7A c.980C>T and ATP7B c.4358G>A. To further elucidate the genetic background of this disease, we used targeted Next Generation Sequencing (NGS) in a cohort of 95 Labrador retrievers to analyze 72 potential modifier genes for variations associated with hepatic copper levels. Variants associated with copper levels were subsequently evaluated in a replication cohort of 144 Labrador retrievers. A total of 44 variants in 25 different genes were identified, of which four showed significant association with copper levels. Of the four variants found associated with hepatic copper levels in the NGS cohort, one was validated in the replication cohort. The non-reference allele of the variant NC_006602.3.g.52434480C>T in RETN resulting in amino-acid change p.Leu7Phe was associated with decreased hepatic copper levels. In humans, resistin is associated with severity of non-alcoholic fatty liver disease, fibrosis, cirrhosis and mitochondrial dysfunction in hepatocytes. Further studies are needed to investigate the biological function of RETN p.Leu7Phe in the development of copper toxicosis in Labrador retrievers.

Highlights

IntroductionCopper (Cu) is an essential trace element, with an important role in many cellular processes [1]
Copper (Cu) is an essential trace element, with an important role in many cellular processes [1].It can be present in two oxidation states Cu(I)/Cu+ and Cu(II)/Cu2+, which provides the ability to act as a recipient or donor for electrons
We previously reported the association of variants of ATP7A and ATP7B with hepatic copper levels in Labrador retrievers

Summary

Introduction

Copper (Cu) is an essential trace element, with an important role in many cellular processes [1]. It can be present in two oxidation states Cu(I)/Cu+ (cuprous ion) and Cu(II)/Cu2+ (cupric ion), which provides the ability to act as a recipient or donor for electrons. Copper is involved in cell metabolism pathways, like the mitochondrial respiratory chain and is essential for the cellular energy metabolism [3]. Copper is absorbed in the small intestine and transported through the portal system to the liver. The liver plays a central role in copper homeostasis and is involved in copper-storage, re-distribution and excretion via the bile [2].

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