Loss-of-function variant in the ovine TMCO6 gene in north country Cheviot sheep with motor neuron disease.

Letko, Anna; Brülisauer, Franz; Häfliger, Irene M; Corr, Eilidh; Scholes, Sandra; Drögemüller, Cord (2023). Loss-of-function variant in the ovine TMCO6 gene in north country Cheviot sheep with motor neuron disease. Genomics, 115(5), p. 110689. Elsevier 10.1016/j.ygeno.2023.110689

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In North Country Cheviot lambs with early-onset progressive ataxia and motor neuron degeneration, whole-genome sequencing identified a homozygous loss-of-function variant in the ovine transmembrane and coiled-coil domains (TMCO6) gene. The familial recessive form of motor neuron disease in sheep is due to a pathogenic 4 bp deletion leading to a 50% protein truncation that is assumed to result in the absence of a functional TMCO6. This uncharacterised protein is proposed to interact with ubiquilin 1which is associated with Alzheimer's disease, whereas sporadic forms of amyotrophic lateral sclerosis are caused by variants in Ubiquilin 2. Our findings provide a first spontaneous animal model for TMCO6, which could have implications in the studies of other comparative neurodegenerative diseases. In addition, these results will allow the design of a genetic test to prevent the occurrence of this fatal disease in the affected sheep population.

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