Role of associated alleles and hypomethylation status in the clinical expression of facioscapulohumeral muscular dystrophy

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat region on 4q35. In addition, epigenetic modifying factors play a role in the complex pathomechanism of the disease. Aims: Introduction of a new diagnostic panel in Hungary for the extended molecular analysis of the disease which also provides new insights into the pathomechanism. Methods: In total, DNA samples of 185 clinically diagnosed FSHD patients and 71 asymptomatic relatives were analyzed by EcoRI and BlnI restriction digestion and Southern blot technique with probe p13-E11. Further investigations of the 4q35 alleles associated with the FSHD phenotype utilized qA and qB probes and a restriction analysis of the proximal D4Z4 unit by detecting a G/C SNP and the methylation status. Results: From the patients analyzed 115 had the D4Z4 repeat contraction, whereas from 71 asymptomatic family members five harbored the pathogenic fragment size. In eight families, prenatal testing had to be offered with an outcome of four affected fetuses. Methylation test was performed in 31 genetically confirmed FSHD patients and hypomethylation status was detected in all cases. All the 115 confirmed patients had 4qA alleles with the G polymorphism. Translocation events between 4q35 and the homologous 10q26 regions were also detected. Conclusion: Molecular diagnosis of FSHD became a routine approach in Hungary thus supporting the work of the clinicians, improving quality of life and genetic counseling of the affected families. The provided results from this research suggest that FSHD is associated with complex epigenetic disease mechanisms. Orv. Hetil., 2011, 152, 1576–1585.

Download Full-text

Disease modifying factors in facioscapulohumeral muscular dystrophy: Protocol of the FSHD-FOCUS study

Neuromuscular Disorders ◽

10.1016/j.nmd.2015.06.110 ◽

2015 ◽

Vol 25 ◽

pp. S214-S215

Author(s):

K. Mul ◽

G. Horlings ◽

R. Lemmers ◽

N. Voermans ◽

S. van der Maarel ◽

...

Keyword(s):

Muscular Dystrophy ◽

Facioscapulohumeral Muscular Dystrophy ◽

Modifying Factors ◽

Disease Modifying

Download Full-text

The Subtelomeric D4Z4 Repeat Instability in Facioscapulohumeral Muscular Dystrophy

Genetic Instabilities and Neurological Diseases ◽

10.1016/b978-012369462-1/50010-7 ◽

2006 ◽

pp. 151-162

Author(s):

SILVÉRE M. VAN DER MAAREL ◽

RUNE R. FRANTS ◽

GEORGE W. PADBERG

Keyword(s):

Muscular Dystrophy ◽

Facioscapulohumeral Muscular Dystrophy ◽

Repeat Instability ◽

D4z4 Repeat

Download Full-text

Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy

Neurology ◽

10.1212/wnl.0000000000009617 ◽

2020 ◽

Vol 94 (23) ◽

pp. e2441-e2447 ◽

Cited By ~ 10

Author(s):

Kohei Hamanaka ◽

Darina Šikrová ◽

Satomi Mitsuhashi ◽

Hiroki Masuda ◽

Yukari Sekiguchi ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Muscular Dystrophy ◽

Target Gene ◽

Disease Gene ◽

Facioscapulohumeral Muscular Dystrophy ◽

Target Gene Expression ◽

D4z4 Repeat ◽

Biopsy Examination ◽

Chromatin Relaxation

ObjectiveFacioscapulohumeral 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.MethodsClinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.ResultsA 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.ConclusionLRIF1 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.

Download Full-text

Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

International Journal of Molecular Sciences ◽

10.3390/ijms21207783 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7783

Author(s):

Tai-Heng Chen ◽

Yan-Zhang Wu ◽

Yung-Hao Tseng

Keyword(s):

Muscular Dystrophy ◽

Early Onset ◽

Case Reports ◽

Facioscapulohumeral Muscular Dystrophy ◽

Clinical Severity ◽

Genetic Diagnostics ◽

Rapid Decline ◽

Novel Treatments ◽

D4z4 Repeat ◽

History Of

Facioscapulohumeral muscular dystrophy (FSHD)—the worldwide third most common inherited muscular dystrophy caused by the heterozygous contraction of a 3.3 kb tandem repeat (D4Z4) on a chromosome with a 4q35 haplotype—is a progressive genetic myopathy with variable onset of symptoms, distribution of muscle weakness, and clinical severity. While much is known about the clinical course of adult FSHD, data on the early-onset infantile phenotype, especially on the progression of the disease, are relatively scarce. Contrary to the classical form, patients with infantile FSHD more often have a rapid decline in muscle wasting and systemic features with multiple extramuscular involvements. A rough correlation between the phenotypic severity of FSHD and the D4Z4 repeat size has been reported, and the majority of patients with infantile FSHD obtain a very short D4Z4 repeat length (one to three copies, EcoRI size 10–14 kb), in contrast to the classical, slowly progressive, form of FSHD (15–38 kb). With the increasing identifications of case reports and the advance in genetic diagnostics, recent studies have suggested that the infantile variant of FSHD is not a genetically separate entity but a part of the FSHD spectrum. Nevertheless, many questions about the clinical phenotype and natural history of infantile FSHD remain unanswered, limiting evidence-based clinical management. In this review, we summarize the updated research to gain insight into the clinical spectrum of infantile FSHD and raise views to improve recognition and understanding of its underlying pathomechanism, and further, to advance novel treatments and standard care methods.

Download Full-text

The coexistence of eight D4Z4 repeat units and FAT1 mutation in facioscapulohumeral muscular dystrophy

Neuromuscular Disorders ◽

10.1016/j.nmd.2017.06.393 ◽

2017 ◽

Vol 27 ◽

pp. S202

Author(s):

K. Kim ◽

J. Lee ◽

H. Park ◽

H. Shin ◽

H. Kim ◽

...

Keyword(s):

Muscular Dystrophy ◽

Facioscapulohumeral Muscular Dystrophy ◽

D4z4 Repeat ◽

Repeat Units

Download Full-text

The D4Z4 Repeat–Mediated Pathogenesis of Facioscapulohumeral Muscular Dystrophy

The American Journal of Human Genetics ◽

10.1086/428361 ◽

2005 ◽

Vol 76 (3) ◽

pp. 375-386 ◽

Cited By ~ 49

Author(s):

Silvère M. van der Maarel ◽

Rune R. Frants

Keyword(s):

Muscular Dystrophy ◽

Facioscapulohumeral Muscular Dystrophy ◽

D4z4 Repeat

Download Full-text

Does DNA Methylation Matter in FSHD?

Genes ◽

10.3390/genes11030258 ◽

2020 ◽

Vol 11 (3) ◽

pp. 258 ◽

Cited By ~ 4

Author(s):

Valentina Salsi ◽

Frédérique Magdinier ◽

Rossella Tupler

Keyword(s):

Dna Methylation ◽

Developmental Disorder ◽

Methylation Status ◽

Disease Status ◽

Facioscapulohumeral Muscular Dystrophy ◽

Icf Syndrome ◽

D4z4 Repeat ◽

Molecular Features ◽

Reliable Marker ◽

Induced Pluripotent

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4.

Download Full-text