Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy

• Published in: Neurology Vol. 94; no. 23; p. e2441
• Main Authors: Hamanaka, Kohei, Šikrová, Darina, Mitsuhashi, Satomi, Masuda, Hiroki, Sekiguchi, Yukari, Sugiyama, Atsuhiko, Shibuya, Kazumoto, Lemmers, Richard J L F, Goossens, Remko, Ogawa, Megumu, Nagao, Koji, Obuse, Chikashi, Noguchi, Satoru, Hayashi, Yukiko K, Kuwabara, Satoshi, Balog, Judit, Nishino, Ichizo, van der Maarel, Silvère M
• Format: Journal Article
• Language: English
• Published: United States 09.06.2020
• Subjects: Biopsy; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cells, Cultured; Chromatin - ultrastructure; Chromosomal Proteins, Non-Histone - metabolism; Chromosomes, Human, Pair 4 - genetics; Codon, Nonsense; Consanguinity; Fibroblasts; Frameshift Mutation; Gene Duplication; Gene Expression Regulation; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Homozygote; Humans; Male; Middle Aged; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophy, Facioscapulohumeral - genetics; Pedigree; Protein Isoforms - genetics; Repetitive Sequences, Nucleic Acid
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000009617

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.