Abstract
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.
Highlights
Neuroaxonal dystrophy (NAD) comprises a clinically and genetically heterogeneous group of neurodegenerative diseases of central nervous system (Hayflick et al 2018)
Array genotypes of 50 k single-nucleotide polymorphism (SNP) markers were available for 14 Swaledale sheep including 5 neuroaxonal dystrophy (NAD)-affected and 3 unaffected lambs, 5 dams and their assumed sire
Based on the known function of PLA2G6 and its role in human and dog neurodegenerative disease, the rarity of the two identified variants in sheep and the perfect co-segregation of the variant alleles with the disease phenotype in the studied pedigree, we conclude that inherited NAD in Swaledale sheep is caused by compound heterozygosity
Summary
Neuroaxonal dystrophy (NAD) comprises a clinically and genetically heterogeneous group of neurodegenerative diseases of central nervous system (Hayflick et al 2018). Molecular Genetics and Genomics (2021) 296:235–242 neuropathological changes involve formation of axonal swellings (spheroids) in specific regions, usually relay nuclei, of the brainstem and spinal cord (Sisó et al 2006). In humans, this condition is usually described as neurodegeneration with brain iron accumulation (NBIA) or infantile neuroaxonal dystrophy (INAD; OMIM PS234200) and is most frequently monogenic recessively inherited. Phospholipase A2 group VI gene (PLA2G6) encodes 85/88 kDa calcium-independent phospholipase A2, an enzyme that catalyzes the hydrolysis of phospholipids to produce free fatty acids, and has a critical role in cell membrane homeostasis (Baburina and Jackowski 1999)
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