Objective: Facioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. FSHD patients 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 if LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2. 

Methods: Clinical examination of an idiopathic FSHD2 patient was combined with pathological 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 knock down of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression.

Conclusions: 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.