Data from: A missense mutation in AGTPBP1 was identified in sheep with a lower motor neuron disease

A type of lower motor neuron (LMN) 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 Ovine SNP50 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 it was the basis for searching for the positional candidate genes. Other homozygous regions shared by all affected sheep spanned eight or fewer SNP loci. The 136-SNP region contained the sheep ATP/GTP-binding protein 1 (AGTPBP1) gene. Mutations in this gene have 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, which induces an Arg to Pro substitution (p.Arg970Pro) at amino-acid 970, a conserved residue for the catalytic activity of AGTPBP1. Genotyping of this mutation showed 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 associated with a LMN disease in a large mammal animal model. Our finding raises the possibility of human patients with the same etiology caused by this gene or other genes in the same pathway of neuronal development.

本研究针对罗姆尼羊中一种以常染色体隐性方式遗传的下运动神经元（lower motor neuron，LMN）病进行了分析，该病的临床特征为出生时外观正常，但在出生后第一周出现进行性肌无力与四肢轻瘫。研究利用Illumina Ovine SNP50 BeadChips，对来自一只携带者公羊的后代羔羊开展全基因组纯合性定位分析，受试群体包含19只确诊患病绵羊，以及11名已知为携带者的患病羔羊亲本。所有患病绵羊均共享2号染色体上一段包含136个连续单核苷酸多态性（single-nucleotide polymorphism，SNP）位点的纯合区域，该区域为寻找位置候选基因提供了依据；其余所有患病绵羊共享的纯合区域所包含的SNP位点均不超过8个。这段包含136个SNP位点的区域内存在绵羊ATP/GTP结合蛋白1（ATP/GTP-binding protein 1，AGTPBP1）基因。已有研究表明，该基因的突变与小鼠的浦肯野细胞变性（Purkinje cell degeneration，pcd）表型相关，这类表型包括共济失调。研究人员在AGTPBP1基因的21号外显子上发现了一处错义突变c.2909G>C，该突变会导致第970位氨基酸发生精氨酸向脯氨酸的替换（p.Arg970Pro），而该位点是维持AGTPBP1催化活性的保守残基。对该突变的基因分型结果显示，在患病个体、携带者、表型正常个体以及无亲缘关系的正常个体中，其基因型与该疾病的常染色体隐性遗传模式完全吻合（吻合率达100%）。本研究首次报道了在大型哺乳动物模型中，突变型AGTPBP1与LMN病存在关联。本研究结果提示，部分人类患者的发病病因可能与该基因或神经元发育通路上的其他基因变异相关。