Kohei Hamanaka1, Darina Šikrová1, Satomi Mitsuhashi1, Hiroki Masuda1, Yukari Sekiguchi1, Atsuhiko Sugiyama1, Kazumoto Shibuya1, Richard J L F Lemmers1, Remko Goossens1, Megumu Ogawa1, Koji Nagao1, Chikashi Obuse1, Satoru Noguchi1, Yukiko K Hayashi1, Satoshi Kuwabara1, Judit Balog1, Ichizo Nishino2, Silvère M van der Maarel1. 1. 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. 2. 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. nishino@ncnp.go.jp.
Abstract
OBJECTIVE: 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 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. METHODS: Clinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies. RESULTS: A 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. CONCLUSION: LRIF1 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.
OBJECTIVE: 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 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. METHODS: Clinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies. RESULTS: A 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. CONCLUSION: LRIF1 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.
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