Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, 08950, Spain.
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, 08950, Spain.
Ann Clin Transl Neurol. 2023 Mar;10(3):408-425. doi: 10.1002/acn3.51731. Epub 2023 Jan 18.
Mutations in ANXA11 cause amyotrophic lateral sclerosis (ALS) and have recently been identified as a cause of multisystem proteinopathy and adult-onset muscular dystrophy. These conditions are adult-onset diseases and result from the substitution of Aspartate 40 (Asp40) for an apolar residue in the intrinsically disordered domain (IDD) of ANXA11. Some ALS-related variants are known to affect ANXA11 IDD; however, the mechanism by which the myopathy occurs is unknown.
Genetic analysis was performed using WES-trio. For the study of variant pathogenicity, we used recombinant proteins, muscle biopsy, and fibroblasts.
Here we describe an individual with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy who carries a new ANXA11 variant at position Asp40 (p.Asp40Ile; c.118_119delGAinsAT). p.Asp40Ile is predicted to enhance the aggregation propensity of ANXA11 to a greater extent than other changes affecting this residue. In vitro studies using recombinant ANXA11 showed abnormal phase separation and confirmed this variant is more aggregation-prone than the ALS-associated variant ANXA11 . The study of the patient's fibroblasts revealed defects in stress granules dynamics and clearance, and muscle histopathology showed a myopathic pattern with ANXA11 protein aggregates. Super-resolution imaging showed aggregates expressed as pearl strips or large complex structures in the sarcoplasm, and as layered subsarcolemmal chains probably reflecting ANXA11 multifunctionality.
We demonstrate common pathophysiology for disorders associated with ANXA11 Asp40 allelic variants. Clinical phenotypes may result from different deleterious impacts of variants upon ANXA11 stability against aggregation, and differential muscle or motor neuron dysfunction expressed as a temporal and tissue-specific continuum.
ANXA11 突变可导致肌萎缩侧索硬化症（ALS），最近被确定为多系统蛋白病和成人起病型肌营养不良症的病因。这些疾病为成人起病，由 ANXA11 无规卷曲结构域（IDD）中天门冬氨酸 40 位（Asp40）被非极性残基取代引起。已知一些与 ALS 相关的变体可影响 ANXA11 IDD；然而，肌病发生的机制尚不清楚。
采用 WES-trio 进行基因分析。为了研究变体的致病性，我们使用了重组蛋白、肌肉活检和成纤维细胞。
在此，我们描述了一位患有严重且快速进展的儿童起病型眼咽型肌营养不良症的个体，其携带位于 Asp40 位置的新 ANXA11 变体（p.Asp40Ile；c.118_119delGAinsAT）。与影响该残基的其他变化相比，p.Asp40Ile 预测会增强 ANXA11 的聚集倾向。使用重组 ANXA11 的体外研究显示异常的相分离，并证实该变体比与 ALS 相关的变体 ANXA11 更易聚集。对患者成纤维细胞的研究显示应激颗粒动力学和清除缺陷，肌肉组织病理学显示肌病模式伴 ANXA11 蛋白聚集。超分辨率成像显示聚集物在肌浆中呈珍珠串或大的复杂结构表达，在细胞膜下呈层状链可能反映 ANXA11 的多功能性。
我们证明了与 ANXA11 Asp40 等位变体相关的疾病存在共同的病理生理学。临床表型可能是由于变体对 ANXA11 稳定性的不同有害影响，以及以时间和组织特异性连续体表达的不同肌肉或运动神经元功能障碍所致。
