Neuropathy target esterase gene mutations cause motor neuron disease
Neuropathy target esterase gene mutations cause motor neuron disease
复制标题
DOI：
10.1016/j.ajhg.2007.12.018
复制
发表时间：
2008-03-01
影响因子：
9.8
通讯作者：
Fink, John K.
中科院分区：
文献类型：
--
作者：
Rainier, Shirley;Bui, Melanie;Fink, John K.
有机磷（OP）化合物促进运动神经元疾病（MND）的可能性得到了对氧磷酶1多态性与肌萎缩侧索硬化症（ALS）的关联以及有机磷化合物诱导的延迟性神经病变（OPIDN）中MND的发生的支持，其中神经病变靶酯酶（NTE）被有机磷酸化抑制。我们评估了一名近亲亲属和一名基因无关的非近亲亲属，其中受影响的受试者表现出进行性痉挛性截瘫和远端肌肉萎缩。受影响的受试者与OPIDN患者和因SPG20/spartin基因突变而导致的Troyer综合征患者相似（通过遗传连锁和SPG20/spartin序列分析排除）。全基因组分析表明，NTE与19p13染色体上一个22 cM的纯合位点（D19S56S ~ D19S884，多点LOD最大值3.28）有连锁关系，该位点已被定位（GenBank AJ004832）。由于NTE在OPIDN中的作用以及我们的患者与OPIDN患者的相似性，NTE成为候选药物。在近亲中受影响的受试者是疾病特异性NTE突变c.3034A -> G的纯合子，该突变破坏了NTE催化结构域的种间保守残基（MI012V）。非近亲家族的受影响对象为复合杂合子：一个等位基因有c.2669G -> A突变，该突变破坏了NTE催化结构域（R890H）的种间保守残基，另一个等位基因有一个插入（c.2946_2947insCAGC），导致移码和蛋白质截断（p.S982fs1019）。不相关的MND患者的疾病特异性、非保守性NTE突变表明，NTE在维持轴突完整性方面的重要性，提高了NTE通路紊乱导致包括ALS在内的其他MND的可能性，并支持NTE异常在神经性OP化合物产生的轴索病中的作用。
The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S56S to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A -> G that disrupted an interspecies conserved residue (MI012V) in NTE's catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G -> A mutation, which disrupts an interspecies conserved residue in NTE's catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTE's importance in maintaining axonal integrity raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds.