Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2
Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2
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DOI：
10.1093/brain/awu356
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发表时间：
2015-02-01
期刊：
影响因子：
14.5
通讯作者：
North, Kathryn N.
中科院分区：
文献类型：
--
作者：
Rossor, Alexander M.;Oates, Emily C.;North, Kathryn N.
脊髓性肌萎缩症是一种下运动神经元疾病，最常见的原因是染色体5 q上SMN 1的隐性突变。无SMN 1突变的病例根据表型进行细分。脊髓性肌萎缩症，以下肢为主，其特征是下肢肌肉无力和消瘦，与腰椎运动神经元数量减少相关，由DYNC 1H 1突变引起，DYNC 1H 1编码动力蛋白-动力蛋白复合物及其货物衔接子之一BICD 2中的微管运动蛋白。我们现在已经从9个不同的家族中确定了32名BICD 2突变患者，为BICD 2疾病的临床表型和自然史提供了详细的见解。BICD 2型脊髓性肌萎缩症，以下肢为主，最常见的表现为运动里程碑延迟和踝关节挛缩。其他特征包括关节弯曲和先天性髋关节脱位。在所有受影响的个体中，虚弱和消瘦以下肢为主，并且通常涉及近端和远端肌肉群。没有感觉神经受累的证据。上运动神经元体征是一个突出的特点，在一个子集的个人，包括一个家庭与专门的成年发作上运动神经元的功能，符合诊断遗传性痉挛性截瘫。在所有队列成员中，下运动神经元特征是静态的或仅缓慢进展的，并且大多数在整个生命中保持走动。6例患者的肌肉MRI显示了一种常见的肌肉受累模式，大多数大腿肌肉存在脂肪沉积，但内收肌和半腱肌除外。肌肉病理学结果高度可变，包括假性肌病特征、神经性特征和微小变化。这六个致病突变，包括一个以前没有报道过的突变，导致BICD 2蛋白的所有三个卷曲螺旋结构域内的氨基酸变化，并包括一个可能的“热点”突变，p.Ser107Leu存在于四个家族中。我们使用最近解决的晶体结构的高度保守区域的果蝇直系同源物的BICD 2进一步探索如何p.Glu774Gly取代抑制BICD 2的Rab 6的结合。总体而言，BICD 2型脊髓性肌萎缩症（以下肢为主）的特征与优先影响腰椎下运动神经元的病理过程一致，伴或不伴额外的上运动神经元受累。在这一迄今为止报道的最大的BICD 2疾病队列中定义表型特征，将有助于在具有相似特征的病例中进行集中的基因检测和过滤下一代测序衍生的变体。
Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p. Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.