The KIT Gene Is Associated with the English Spotting Coat Color Locus and Congenital Megacolon in Checkered Giant Rabbits (Oryctolagus cuniculus)

Abstract

The English spotting coat color locus in rabbits, also known as Dominant white spotting locus, is determined by an incompletely dominant allele (En). Rabbits homozygous for the recessive wild-type allele (en/en) are self-colored, heterozygous En/en rabbits are normally spotted, and homozygous En/En animals are almost completely white. Compared to vital en/en and En/en rabbits, En/En animals are subvital because of a dilated (“mega”) cecum and ascending colon. In this study, we investigated the role of the KIT gene as a candidate for the English spotting locus in Checkered Giant rabbits and characterized the abnormalities affecting enteric neurons and c-kit positive interstitial cells of Cajal (ICC) in the megacolon of En/En rabbits. Twenty-one litters were obtained by crossing three Checkered Giant bucks (En/en) with nine Checkered Giant (En/en) and two en/en does, producing a total of 138 F1 and backcrossed rabbits. Resequencing all coding exons and portions of non-coding regions of the KIT gene in 28 rabbits of different breeds identified 98 polymorphisms. A single nucleotide polymorphism genotyped in all F1 families showed complete cosegregation with the English spotting coat color phenotype (θ = 0.00 LOD = 75.56). KIT gene expression in cecum and colon specimens of En/En (pathological) rabbits was 5–10% of that of en/en (control) rabbits. En/En rabbits showed reduced and altered c-kit immunolabelled ICC compared to en/en controls. Morphometric data on whole mounts of the ascending colon showed a significant decrease of HuC/D (P<0.05) and substance P (P<0.01) immunoreactive neurons in En/En vs. en/en. Electron microscopy analysis showed neuronal and ICC abnormalities in En/En tissues. The En/En rabbit model shows neuro-ICC changes reminiscent of the human non-aganglionic megacolon. This rabbit model may provide a better understanding of the molecular abnormalities underlying conditions associated with non-aganglionic megacolon.

Genes and light: many years later

“…ig1-3 bind to a KiT ligand (KiTLG or SCF) with high affinity and trigger dimerization, in which ig4 plays a significant role. En/En homozygotes are characterized by reduced viability due to development of megacolon, similar to the anomaly observed in foxes homozygous for the Georgian white mutation (Fontanesi et al, 2014). Fig.…”

“…Этoт тип пятнистости тoже демонстрирует неполную доминатность, низкую жизнеспособность гомозигот в раннем постнатальном периоде, связанную с редуцированной экспрессией KIT в ICC кишечника (рис. 5), что затрудняeт перистальтику и, как следствие, ведет к развитию мегаколона (Fontanesi et al, 2014). Хотя твердо установлено, что изменение генa KIT у кроликов ответственнo за формирование характерного фенотипа, молекулярная природа этой мутации пока неизвестна.…”

“…Хотя твердо установлено, что изменение генa KIT у кроликов ответственнo за формирование характерного фенотипа, молекулярная природа этой мутации пока неизвестна. Все до сих пор обнаруженные SNP (single nucleotide polymorphism), за исключением одного, являются синонимическими заменами, а единственная несинонимическая замена в 4 экзоне представляется авторам исследования маловероятнoй в качестве каузальной мутации (Fontanesi et al, 2014). Таким образом, остается невыясненным, какое именно структурное или функциональное изменение ведет к формированию пятнистости у кролика.…”

A Frameshift Mutation in KIT is Associated with White Spotting in the Arabian Camel

“…KIT , v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolo g, is one of the most commonly implicated genes for white spotting phenotypes in animals [17,18,19,20,21,22,23,24]. There are four reported frameshift mutations in the domestic horse, all of which were associated with extensive white spotting [17,25,26].…”

La génomique du lapin : avancées, applications et perspectives

“…En raison de l'importance économique de la croissance et de la production de viande, la plupart des études de gènes candidats chez le lapin porte sur ce groupe de caractères. Fontanesi et al (2011Fontanesi et al ( , 2012a, Fontanesi et al (2012bFontanesi et al ( , 2014 et Fontanesi et al (2016) ont étudié le caractère de croissance le plus couramment enregistré et sélectionné dans les populations commerciales de production de viande, le poids à 70 jours. D'autres auteurs (Peng et al, 2013 ;Zhang et al, 2013aZhang et al, , 2013cLiu et al, 2014 ;Wang et al, 2015) ont étudié des caractères de croissance, de carcasse et de qualité de viande mesurés à des âges différents.…”