Department Neurological Sciences, ‘Dino Ferrari’ Center,Universita` degli Studi di Milano, Milan, Italy.
J Neurol Neurosurg Psychiatry. 2011 Nov;82(11):1239-43. doi: 10.1136/jnnp.2011.242313. Epub 2011 May 25.
Optineurin (OPTN), a causative gene of hereditary primary open-angle glaucoma, has been recently associated with amyotrophic lateral sclerosis (ALS) with mainly autosomal recessive, but also dominant, traits. To further define the contribution of OPTN gene in ALS, we performed a mutational screening in a large cohort of Italian patients.
A group of 274 ALS patients, including 161 familial (FALS) and 113 sporadic (SALS) cases, were screened for OPTN mutations by direct sequencing of its coding sequence. All patients fulfilled the El Escorial criteria for probable or definite ALS and were negative for mutations in SOD1, ANG, TARDBP and FUS/TLS genes.
The genetic analysis revealed six novel variants in both FALS and SALS patients, all occurring in an heterozygous state. We identified three missense (c.844A→C p.T282P, c.941A→T p.Q314L, c.1670A→C p.K557T), one nonsense (c.67G→T p.G23X) and two intronic mutations (c.552+1delG, c.1401+4A→G). The intronic c.552+1delG variant determined a splicing defect as demonstrated by mRNA analysis. All mutations were absent in 280 Italian controls and over 6800 worldwide glaucoma patients and controls screened so far. The clinical phenotype of OPTN-mutated patients was heterogeneous for both age of onset and disease duration but characterised by lower-limb onset and prevalence of upper motor neuron signs.
In this cohort, OPTN mutations were present both in FALS (2/161), accounting for 1.2% cases, and in SALS patients (4/113), thereby extending the spectrum of OPTN mutations associated with ALS. The study further supports the possible pathological role of optineurin protein in motor neuron disease.
视神经病变诱导蛋白（OPTN）是遗传性开角型青光眼的致病基因，最近与肌萎缩性侧索硬化症（ALS）相关联，其主要表现为常染色体隐性遗传，但也有显性遗传特征。为了进一步明确 OPTN 基因在 ALS 中的作用，我们对一组意大利患者进行了突变筛查。
对 274 例 ALS 患者（包括 161 例家族性 ALS（FALS）和 113 例散发性 ALS（SALS））进行 OPTN 基因突变的直接测序筛选。所有患者均符合 El Escorial 标准，为可能或明确的 ALS，且 SOD1、ANG、TARDBP 和 FUS/TLS 基因均无突变。
遗传分析显示，在 FALS 和 SALS 患者中均发现了 6 个新的变异，均为杂合状态。我们鉴定了 3 个错义突变（c.844A→C p.T282P、c.941A→T p.Q314L、c.1670A→C p.K557T）、1 个无义突变（c.67G→T p.G23X）和 2 个内含子突变（c.552+1delG、c.1401+4A→G）。内含子 c.552+1delG 变异导致剪接缺陷，这通过 mRNA 分析得到证实。到目前为止，所有突变在 280 名意大利对照者和超过 6800 名全球青光眼对照者中均未检出。OPTN 突变患者的临床表型在发病年龄和疾病持续时间上存在异质性，但以下肢起病和上运动神经元体征的发生率为特征。
在该队列中，FALS（2/161）和 SALS 患者（4/113）中均存在 OPTN 突变，占病例的 1.2%，从而扩展了与 ALS 相关的 OPTN 突变谱。该研究进一步支持 OPTN 蛋白在运动神经元疾病中的潜在病理作用。
