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

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.

Clinicopathological and pedigree investigation of a novel spinocerebellar neurological disease in juvenile Quarter Horses in North America

“…The other inherited axonopathies (central and peripheral axonopathy of Maine-Anjou cattle and neuroaxonal dystrophy of sheep) have lesions extending into the cerebrum and/or cerebellum. 22,23 Central and peripheral axonopathy of Rouge-des-Pres cattle presents as a progressive ataxia most prominently affecting the pelvic limbs, and affected calves consistently have a swaying motion of the hindquarters that leads to loss of balance. 10 Signs begin between 5 and 16 weeks and end in recumbency within 1-3 weeks following onset of signs.…”

MFSD2A frameshift variant in Kerry Hill sheep with microcephaly

“…Nevertheless, the Sheep Gene Expression Atlas of the sheep FAANG initiative shows that MFSD2A is expressed in various tissues, including the central nervous system of adult sheep as well as the fetal brain (Clark et al., 2017). Our study is the first report of the precise underlying pathogenesis of an inherited form of microcephaly in sheep and provides another successful example of the WGS‐based precision medicine approach detecting pathogenic variants associated with rare neurodegenerative diseases (Letko et al., 2021). Ultimately, our data will enable genetic testing to prevent unintentional breeding of more affected lambs.…”

Independent COL17A1 Variants in Cats with Junctional Epidermolysis Bullosa

“…RNA was extracted from skin samples of case 2 and an unaffected control cat using the RNeasy Fibrous Tissue Mini Kit (Qiagen, Hilden, Germany). Tissue processing, RNA extraction, and reverse transcription into cDNA were performed as previously described using the SuperScript IV Reverse Transcriptase kit (Thermo Fisher Scientific) [36]. A 518 bp PCR product was amplified with AmpliTaqGold360Mastermix (Thermo Fisher Scientific) from cDNA using a forward primer spanning exon boundaries 7 and 8, and a reverse primer spanning exon boundaries 12 and 13 of the COL17A1 gene (Table S2).…”