PDF(Pubmed)
Abstract：
Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2-3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7-11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.
摘要：
MUSK基因功能变异的双等位基因缺失导致两种等位基因疾病：1）先天性肌无力综合征（CMS；OMIM616325），一种神经肌肉疾病，其严重程度从严重的新生儿发作无力到轻度的成人发作无力和2）胎儿运动障碍变形序列（FADS；OMIM208150），一种以胎儿严重肌肉无力为特征的妊娠损失。MUSK基因编码肌肉特异性激酶(MuSK),参与神经肌肉接头发育的受体酪氨酸激酶。在这里，我们报告了一例新生儿发病的MUSK相关CMS，该患者在MUSK基因中具有复合杂合缺失，包括：1）外显子2-3的缺失，导致缺乏Ig1结构域的框内MuSK蛋白；2）外显子7-11的缺失，导致框外截短的MuSK蛋白。已经在结构上阐明了MuSK蛋白的各个结构域;然而,由机器学习算法生成的完整的MuSK结构具有明显的不准确性。我们修改了预测的AlphaFold结构，并整合了先前报道的结构域特异性结构数据，以提示在两个位置（Ig1和跨膜结构域）二聚化的MuSK蛋白。我们分析了MUSK中已知的致病变异，以发现结构域特异性基因型-表型相关性;导致蛋白质表达丢失的变异，Ig1结构域的破坏，或Dok-7结合与最严重的表型相关。提供了一个概念模型来解释在Ig1变体中看到的严重表型以及我们的患者对吡啶斯的明的不良反应。
