Sporadic occurrences of neurodegenerative disorders including neuroaxonal dystrophy (NAD) have been previously reported in sheep. However, so far no causative genetic variant has been found for ovine NAD. The aim of this study was to characterize the phenotype and the genetic aetiology of an early-onset neurodegenerative disorder observed in several lambs of purebred Swaledale sheep, a native English breed. Affected lambs showed progressive ataxia and stiff gait and subsequent histopathological analysis revealed the widespread presence of axonal spheroid indicating neuronal degeneration. Thus, the observed clinical phenotype could be explained by a novel form of NAD. After SNP genotyping and subsequent linkage mapping within a paternal half-sib pedigree with a total of five NAD-affected lambs, we identified two loss-of-function variants by whole-genome sequencing in the ovine PLA2G6 gene situated in a NAD-linked genome region on chromosome 3. All cases were carriers of a compound heterozygous splice site variant in intron 2 and a nonsense variant in exon 8. Herein we present evidence for the occurrence of a familial novel form of recessively inherited NAD in sheep due to allelic heterogeneity at PLA2G6. This study reports two pathogenic variants in PLA2G6 causing a novel form of NAD in Swaledale sheep which enables selection against this fatal disorder.

先前已经在绵羊中偶发了神经退行性疾病，包括神经轴索营养不良（NAD）。然而，到目前为止，尚未发现绵羊NAD的致病性遗传变异。这项研究的目的是表征在几只纯种的Swaledale绵羊羔羊（一种英国本土品种）中观察到的早发性神经退行性疾病的表型和遗传病因。患病的羔羊表现出进行性共济失调和僵硬的步态，随后的组织病理学分析显示轴突椭球的广泛存在，表明神经元变性。因此，观察到的临床表型可以用一种新型的NAD来解释。在父本的半同胞谱系中对SNP进行基因分型并随后进行连锁定位后，总共有5只受NAD影响的羔羊，PLA2G6。这项研究报告了PLA2G6中的两种致病变异体，它们在Swaledale绵羊中引起了一种新型的NAD形式，从而可以选择对抗这种致命疾病。