Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation.
Isolated inclusion body myopathy caused by a multisystem proteinopathy-linked hnRNPA1 mutation.
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DOI：
10.1212/nxg.0000000000000023
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Aoki M
中科院分区：
文献类型：
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作者：
Izumi R;Warita H;Niihori T;Takahashi T;Tateyama M;Suzuki N;Nishiyama A;Shirota M;Funayama R;Nakayama K;Mitsuhashi S;Nishino I;Aoki Y;Aoki M
旨在确定 2 个家族中常染色体显性遗传的孤立性包涵体肌病 (IBM) 的遗传原因。使用异质核核糖核蛋白 A1 基因 (hnRNPA1) 的全外显子组和桑格测序进行遗传研究。通过神经系统检查、肌肉成像和肌肉活检评估2个家族患者的临床和病理特征。我们在 2 个 IBM 家族中发现了 hnRNPA1 中的 p.D314N 错义突变，该突变也导致家族性肌萎缩侧索硬化症。受影响的人在 40 多岁时出现肌肉无力，并慢慢发展为肢带型。对受影响个体的进一步评估显示，没有明显的运动神经元功能障碍、认知障碍或骨骼异常。肌肉病理学与 IBM 相一致，没有明显的神经源性变化和炎症。多项免疫组织化学分析显示 hnRNPA1 的细胞质聚集与自噬体和肌核密切相关。此外，异常积累的特点是与泛素、sequestome-1/p62、含缬洛辛的蛋白/p97 和多种 RNA 结合蛋白 (RBP) 共聚集。本研究扩展了 hnRNPA1 相关多系统蛋白病的临床表型。 hnRNPA1（可能还有 hnRNPA2B1）的突变将导致孤立的 IBM 具有纯肌肉表型。尽管选择性骨骼肌参与的机制仍有待阐明，但免疫组织化学结果表明突变的 hnRNPA1 广泛隔离了 RBP。
To identify the genetic cause of isolated inclusion body myopathy (IBM) with autosomal dominant inheritance in 2 families. Genetic investigations were performed using whole-exome and Sanger sequencing of the heterogeneous nuclear ribonucleoprotein A1 gene (hnRNPA1). The clinical and pathologic features of patients in the 2 families were evaluated with neurologic examinations, muscle imaging, and muscle biopsy. We identified a missense p.D314N mutation in hnRNPA1, which is also known to cause familial amyotrophic lateral sclerosis, in 2 families with IBM. The affected individuals developed muscle weakness in their 40s, which slowly progressed toward a limb-girdle pattern. Further evaluation of the affected individuals revealed no apparent motor neuron dysfunction, cognitive impairment, or bone abnormality. The muscle pathology was compatible with IBM, lacking apparent neurogenic change and inflammation. Multiple immunohistochemical analyses revealed the cytoplasmic aggregation of hnRNPA1 in close association with autophagosomes and myonuclei. Furthermore, the aberrant accumulation was characterized by coaggregation with ubiquitin, sequestome-1/p62, valosin-containing protein/p97, and a variety of RNA-binding proteins (RBPs). The present study expands the clinical phenotype of hnRNPA1-linked multisystem proteinopathy. Mutations in hnRNPA1, and possibly hnRNPA2B1, will be responsible for isolated IBM with a pure muscular phenotype. Although the mechanisms underlying the selective skeletal muscle involvement remain to be elucidated, the immunohistochemical results suggest a broad sequestration of RBPs by the mutated hnRNPA1.