We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD.
To compare the clinical features of patients showing a classical phenotype of facioscapulohumeral muscular dystrophy (FSHD) with genetic and epigenetic characteristics of the FSHD1 and FSHD2 loci D4Z4 and <i>SMCHD1</i>.
However, although human mutations in <i>SMCHD1</i> are associated with congenital arhinia and facioscapulohumeral muscular dystrophy type 2 (FSHD2), the diseases do not show a sex-specific bias, despite the essential nature of XCI in humans.
FSHD is generally associated with the contraction of D4Z4 macrosatellite repeats on 4q35 chromosome or mutations in SMCHD1, which are responsible of the toxic expression of DUX4 in muscle tissue.
SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.
To determine whether congenital arhinia/Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2 seemingly unrelated disorders both caused by heterozygous pathogenic missense variants in the <i>SMCHD1</i> gene, might represent different ends of a broad single phenotypic spectrum associated with SMCHD1 dysfunction.
Facioscapulohumeral muscular dystrophy, known in genetic forms FSHD1 and FSHD2, is associated with D4Z4 repeat array chromatin relaxation and somatic derepression of DUX4 located in D4Z4.
Recently, heterozygous mutations in <i>SMCHD1</i> have been reported in two disparate disorders: facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS).
FSHD type 1 (FSHD1) is associated with pathogenic D4Z4 repeat array contraction, while FSHD type 2 (FSHD2) is associated with SMCHD1 variants (a chromatin modifier gene that maps to the short arm of chromosome 18).
The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation.
Facioscapulohumeral muscular dystrophy (FSHD) 2 is caused by a combination of heterozygous structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) mutation plus DNA hypomethylation on D4Z4.
Digenic inheritance of a <i>SMCHD1</i> mutation and a moderately sized D4Z4 repeat on a facioscapulohumeral muscular dystrophy (FSHD) permissive genetic background of chromosome 4 can cause FSHD type 2 (FSHD2).
Structural maintenance of chromosome flexible domain containing 1 (Smchd1) is a chromatin regulatory gene for which mutations are associated with facioscapulohumeral muscular dystrophy and arhinia.
Facioscapulohumeral muscular dystrophy is caused by incomplete repression of the transcription factor DUX4 in skeletal muscle as a consequence of D4Z4 macrosatellite repeat contraction in chromosome 4q35 (FSHD1) or variants in genes encoding D4Z4 chromatin repressors (FSHD2).
Facioscapulohumeral muscular dystrophy (FSHD) is in most cases caused by a contraction of the D4Z4 macrosatellite repeat on chromosome 4 (FSHD1) or by mutations in the SMCHD1 or DNMT3B gene (FSHD2).
Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.
This working hypothesis for FSHD pathogenesis highlights the intrinsic epigenetic nature of the molecular mechanism underlying FSHD as well as the pathogenic pathway connecting FSHD1 and FSHD2.
FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation.