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Abstract：
The von Willebrand Factor A domain containing 1 protein, encoded by VWA1, is an extracellular matrix protein expressed in muscle and peripheral nerve. It interacts with collagen VI and perlecan, two proteins that are affected in hereditary neuromuscular disorders. Lack of VWA1 is known to compromise peripheral nerves in a Vwa1 knock-out mouse model. Exome sequencing led us to identify bi-allelic loss of function variants in VWA1 as the molecular cause underlying a so far genetically undefined neuromuscular disorder. We detected six different truncating variants in 15 affected individuals from six families of German, Arabic, and Roma descent. Disease manifested in childhood or adulthood with proximal and distal muscle weakness predominantly of the lower limbs. Myopathological and neurophysiological findings were indicative of combined neurogenic and myopathic pathology. Early childhood foot deformity was frequent, but no sensory signs were observed. Our findings establish VWA1 as a new disease gene confidently implicated in this autosomal recessive neuromyopathic condition presenting with child-/adult-onset muscle weakness as a key clinical feature.
摘要：
vonWillebrand因子A结构域含有1个蛋白，由VWA1编码，是在肌肉和周围神经中表达的细胞外基质蛋白。它与胶原蛋白VI和Perlecan相互作用，在遗传性神经肌肉疾病中受到影响的两种蛋白质。已知缺乏VWA1会损害Vwal敲除小鼠模型中的外周神经。外显子组测序使我们确定了VWA1中功能变体的双等位基因丧失，这是迄今为止遗传上未定义的神经肌肉疾病的分子原因。我们在来自六个德国家族的15个受影响的个体中检测到六种不同的截断变体，阿拉伯语,罗马血统。表现在儿童或成年期的疾病，主要是下肢的近端和远端肌肉无力。肌病理学和神经生理学的发现表明神经源性和肌病病理学的结合。儿童早期足部畸形很常见，但没有观察到感官症状。我们的发现将VWA1确立为一种新的疾病基因，该基因与这种常染色体隐性遗传性神经肌病有关，以儿童/成人发作的肌肉无力为主要临床特征。
