A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation
A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation
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DOI：
10.1002/ana.22684
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发表时间：
2012-04-01
影响因子：
11.2
通讯作者：
Viollet, Louis
中科院分区：
文献类型：
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作者：
Blumen, Sergiu C.;Astord, Stephanie;Viollet, Louis
目的：远端遗传性运动神经病 (dHMN) 是一组临床和遗传上异质性的疾病，其特征是由于脊髓运动神经元进行性退化，导致四肢远端肌肉无力和萎缩。我们在这里报告了一种新的罕见 dHMN 变体，在一个来自摩洛哥的犹太大家庭中具有常染色体隐性遗传。该病的特点是下肢瘫痪为主，成年早期发病。我们对该家族进行了遗传研究，以鉴定和表征引起突变的特征。方法：对候选基因进行纯合性作图策略和测序。对患者成纤维细胞进行表达研究。在运动神经元疾病的细胞模型上进行了功能实验。结果：我们将疾病定位到 2q34-q36.1 染色体区域，并鉴定了基因 HSJ1 (DNAJB2) 中的纯合剪接突变，降低了 2 个主要亚型 HSJ1a 和 HSJ1b 的表达。在神经元细胞模型中，HSJ1a 和 HSJ1b 的过表达减少了突变 SOD1-A4V 诱导的包涵体形成。解释：HSJ1 是 HSP40/DNAJ 共伴侣家族的神经元富集成员。先前的研究表明，HSP40 蛋白在动物模型和人类疾病中多种神经元类型的蛋白质聚集和神经变性中发挥着至关重要的作用。有趣的是，这种导致 HSJ1 功能丧失的突变与纯粹的下运动神经元疾病有关，强烈表明 HSJ1 在运动神经元中也发挥着重要且特定的作用。安神经学 2012； 71：509-519
Objective: Distal hereditary motor neuropathies (dHMN) form a clinically and genetically heterogeneous group of disorders, characterized by muscle weakness and atrophy predominating at the distal part of the limbs, due to the progressive degeneration of motor neurons in the spinal cord. We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset. We performed a genetic study in this family to identify and characterized the causing mutation.Methods: Homozygosity mapping strategy and sequencing of the candidate genes were performed. Expression studies were made on patient fibroblasts. Functional experiments were performed on a cellular model of motor neuron disease.Results: We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b. Overexpression of both HSJ1a and HSJ1b reduced inclusion formation induced by the mutated SOD1-A4V in a neuronal cellular model.Interpretation: HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family. Previous studies have shown that HSP40 proteins play a crucial role in protein aggregation and neurodegeneration in several neuronal types, in animal models and human diseases. Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons. ANN NEUROL 2012; 71: 509-519