Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy.

Letko, Anna; Strugnell, Ben; Häfliger, Irene M.; Paris, Julia M.; Waine, Katie; Drögemüller, Cord; Scholes, Sandra (2021). Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy. Molecular genetics and genomics : MGG, 296(1), pp. 235-242. Springer 10.1007/s00438-020-01742-1

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH) > Institute of Genetics
05 Veterinary Medicine > Department of Clinical Research and Veterinary Public Health (DCR-VPH)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Letko, Anna; Häfliger, Irene Monika; Paris, Julia Maria and Drögemüller, Cord

Subjects:

500 Science > 590 Animals (Zoology)
600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1617-4615

Publisher:

Springer

Language:

English

Submitter:

Cord Drögemüller

Date Deposited:

11 Nov 2020 09:59

Last Modified:

13 Mar 2021 11:42

Publisher DOI:

10.1007/s00438-020-01742-1

PubMed ID:

33159255

Uncontrolled Keywords:

Compound heterozygosity Neurogenetic disorder Ovis aries Precision medicine Rare disease

BORIS DOI:

10.7892/boris.147885

URI:

https://boris.unibe.ch/id/eprint/147885

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