From the Department of Neuromuscular Research (K.H., S.M., M.O., S.N., I.N.), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurology (K.H.), Graduate School of Medicine, Kyoto University, Japan; Department of Human Genetics (D.Š., R.J.L.F.L., R.G., J.B., S.M.M.), Leiden University Medical Center, the Netherlands; Department of Clinical Development (S.M., I.N.), Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (H.M., Y.S., A.S., K.S., S.K.), Graduate School of Medicine, Chiba University; Department of Biological Sciences (K.N., C.O.), Graduate School of Science, Osaka University; and Department of Pathophysiology (Y.K.H.), Tokyo Medical University, Tokyo, Japan.
Neurology. 2020 Jun 9;94(23):e2441-e2447. doi: 10.1212/WNL.0000000000009617. Epub 2020 May 28.
Facioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded gene in skeletal muscle. In this study, we tested the hypothesis whether , a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2.
Clinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.
A homozygous mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in and DUX4 target gene expression.
is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate expression in skeletal muscle.
面肩肱型肌营养不良症（FSHD）是一种异质性疾病，主要表现为进行性面肌和肩胛带肌无力。FSHD 患者要么在 4q35 染色体上有 D4Z4 重复序列的收缩，要么在 D4Z4 染色质修饰物 SMCHD1 和 DNMT3B 中发生突变，这两种突变都会导致 D4Z4 染色质松弛和 D4Z4 编码的 基因在骨骼肌中的异常表达。在这项研究中，我们检验了假说，即已知的 SMCHD1 蛋白相互作用物 是否是特发性 FSHD2 的疾病基因。
对一名特发性 FSHD2 患者进行临床检查，结合病理肌肉活检检查以及遗传、表观遗传和分子研究。
在一名临床表型与 FSHD 一致的患者中发现了一个纯合的 突变。该突变导致 LRIF1 蛋白的长异构体缺失，D4Z4 染色质松弛，以及 和 DUX4 靶基因在肌核中的表达，所有这些都是 FSHD 的分子和表观遗传特征。LRIF1 被证实与 D4Z4 重复序列结合，在肌肉细胞中敲低 LRIF1 长异构体导致 和 DUX4 靶基因的表达。
是 FSHD2 的一个真正的疾病基因。本研究进一步证实了一个统一的遗传机制，即 FSHD 是由 D4Z4 染色质松弛引起的，导致 在骨骼肌中的异常表达。
