A Heritable AGTPBP1 Missense Mutation is Responsible for a Lower Motor Neuron Disease in Romney Sheep

A type of lower motor neuron disease inherited as autosomal recessive in Romney sheep was characterized with normal appearance at birth, but with progressive weakness and tetraparesis after the first week of life.  Here we carried out genome-wide homozygosity mapping using Illumina OvineSNP50 BeadChips on lambs descended from one carrier ram, including 19 sheep diagnosed as affected and 11 of their parents that were therefore known carriers.  A homozygous region of 136 consecutive single-nucleotide polymorphism (SNP) loci on chromosome 2 was common to all affected sheep and was the basis for the search for positional candidate genes.  Other homozygous regions shared by all affected sheep spanned 8 or fewer SNP loci.  The 136-SNP-region contained the sheep homologous AGTPBP1 gene.  The ATP/GTP-binding protein 1 gene (Agtpbp1) has been shown to be related to Purkinje cell degeneration (pcd) phenotypes including ataxia in mice.  One missense mutation c.2909G>C on exon 21 of AGTPBP1 was discovered to induce an Arg to Pro substitution (p.Arg970Pro) at amino acid 970, which is a conserved residue for the catalytic activity of AGTPBP1.  Genotyping this mutation showed a 100% concordant rate with the recessive pattern of inheritance in affected, carrier, phenotypically normal and unrelated normal individuals.  This is the first report showing a mutant AGTPBP1 is responsible for a lower motor neuron disease in a large mammal animal model.  Our findings raise the possibility of human patients with the same etiology, caused by this gene or other genes in the same pathway of neuronal development.