Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy
Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy
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DOI：
10.1212/wnl.0000000000009617
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发表时间：
2020-06-09
期刊：
影响因子：
9.9
通讯作者：
van der Maarel, Silvere M.
中科院分区：
文献类型：
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作者：
Hamanaka, Kohei;Sikrova, Darina;van der Maarel, Silvere M.
面肩肱型肌营养不良症（FSHD）是一种异质性疾病，主要特征是进行性面部和肩胛肌无力。FSHD患者染色体4q35上的D4Z4重复序列收缩或D4Z4染色质修饰剂SMCHD1和DNMT3B突变，均导致D4Z4染色质松弛和骨骼肌中D4Z4编码的DUX4基因的不适当表达。在这项研究中，我们测试的假设是否LRIF1，一个已知的SMCHD1蛋白相互作用，是一个疾病基因的特发性FSHD 2.MethodsClinical检查的患者与特发性FSHD 2结合病理肌肉活检检查和遗传，表观遗传，和分子study.ResultsA纯合子LRIF1突变被确定在一个患者的临床表型与FSHD一致。该突变导致LRIF1蛋白的长同种型、D4Z4染色质松弛以及DUX4和DUX4靶基因在肌核中表达的缺失，这些都是FSHD的分子和表观遗传学标志。结论LRIF1是FSHD 2的致病基因，其基因表达与D4Z4重复序列的结合有关。这项研究进一步加强了统一的遗传机制，该机制假设FSHD是由D4Z4染色质松弛引起的，导致骨骼肌中DUX4表达不当。
ObjectiveFacioscapulohumeral 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 DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2.MethodsClinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.ResultsA homozygous LRIF1 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 DUX4 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 DUX4 and DUX4 target gene expression.ConclusionLRIF1 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 DUX4 expression in skeletal muscle.