Connexion

GENATLAS PHENOTYPE

last update : 01-06-2016

Symbol	FSHMD1A
Location	4q35
HGNC id	3966
Name	facioscapulohumeral muscular dystrophy, 1A
Other name(s)	Landouzy-Dejerine muscular dystrophy
Other symbol(s)	FMD, FSHD, FSHD1A, FSHD1
Main clinical features	a progressive wasting of the facial, shoulder and upper-arm muscles, including form with sensoryneural hearing loss or tortuosity of retinal arterioles displaying substantial inter and intrafamilial variation, deletion (mental retardation and epilepsy) presence of a small number of D4Z4 repeats is crucial to the process leading to the disease (PMID: 19339494)) peripheral retinal vascular abnormality belonging morphologically and clinically to a class of developmental 'retinal hypovasculopathies' caused by abnormalities of 'Wnt' signalling (PMID: 21377364))
Genetic determination	autosomal dominant
Prevalence	7p 100000
Related entries	. form with spinal muscular atrophy . FSHMD2A shows digenic inheritance,is caused by the combination of a heterozygous mutation in the SMCHD1 gene on chromosome 18p and presence of a haplotype on chromosome 4 that is permissive for DUX4 expression (PMID: 24075187)
Function/system disorder	neuromuscular
Type	disease

Mechanism(s)

Gene mutation	Effect	Comments

deletion		deletion of an integral number of tandem 3.3 kb repeats, D4Z4, 4 to 7 repeats in te common form
deletion		8 to 10 in the milder form
deletion		1 to 3 in early onset, severe disease
other		contraction of the D4Z4 array contributes to FSHD physio-pathology by acting as a CTCF-dependent insulator in patients
	under-expression	4qter D4Z4 region is hypomethylated in both 4q-linked and phenotypic FSHD, with loss of both histone H3K9 trimethylation and HP1gamma/cohesin binding (PMID: 19593370)

Remark(s)

deletion of an integral number of tandem 3.3 kb repeats, D4Z4 associated exclusively with 4qA allele (in the region distal to D4Z4), with hypomethylation of D4Z4 (also in FSHD with unaltered D4Z4), may be a nuclear enveloppe disorder (changes in the DNA-protein interactions at the nuclear envelope affecting signaling pathway)

DUX4-containing D4Z4 elements are present at high and variable copy number on 4q35 with 11 to >100 repeats in controls, but in FSHD, one allele is reduced in size to 1-10 repeats, which is accompanied by a change in chromatin packaging into a less repressive state (PMID: 21110847))

proximal unit of D4Z4 is significantly hypomethylated in affected and asymptomatic carriers, while in type-2 FSHD, a form of the disease that is not linked to contractions of D4Z4 repeats at 4q35, both alleles are significantly hypomethylated (PMID: 19339494))

may be caused by transcriptional dysregulation of multiple genes, in cis and in trans, different in affected patients compared to asymptomatic related carriers (PMID: 19339494))

specific loss of histone H3 lysine 9 trimethylation and CBX3/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD) (PMID: 19593370))

represents the first human disease to be associated with the incomplete developmental silencing of a retrogene array (DUX4) normally expressed early in development (PMID: 21060811))

current genetic signature of FSHD is a common polymorphism and only half of FSHD probands carry this molecular signature (PMID: 22482803))

fetuses carrying an FSHD-linked genotype have an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect (PMID: 23777630))

modifier role for SMCHD1 in FSHMD1A, and carriers of the FSHMD1A allele without the SMCHD1 mutation were only mildly affected (PMID: 24075187))

Genotype/Phenotype correlations

correlated with EcoR1 fragment size at D4F104S1 locus (subtelomeric rearrangement between 10q26 and 4q35 determining a reduction in the critical number of repeats (1-9vs) required for gene function), severe phenotype associated with large10-11kDa fragment (very short fragment sizes of the D4Z4 repeat associated to severe phenotype in infantile facioscapulohumeral muscular dystrophy)

contracted D4Z4 allele and a large proximal deletion associated to severe form

first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array (combination of inefficient chromatin silencing of the D4Z4 repeat and inappropriate DUX4 protein expression in muscle cells) (PMID: 21288772))

may be the first known human disease in which telomere position effects (TPE) contributes to age-related phenotype (PMID: 23644600))

mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of Facioscapulohumeral Dystrophy (FSHMD1A, FSHD2) (PMID: 27153398))