Facioscapulohumeral dystrophy (FSHD) is a common muscular dystrophy characterized by initial weakness of the facial, shoulder and upper arm muscles but progressing to affect almost all skeletal muscles.
In families with the most frequent genetic cause of the disease (FSHD1), a contraction of the polymorphic D4Z4 macrosatellite repeat array on a specific FSHD-permissive haplotype of chromosome 4q, the disease segregates as a dominant trait.
In a small proportion of cases, the disease is caused by mutations in SMCHD1, a member of the condensin/cohesin family of chromatin compaction complexes that binds to the D4Z4 repeat array. In these FSHD2 families, the disease shows a more complex digenic inheritance because the mutation of SMCHD1 on chromosome 18 segregates independently from the FSHD-permissive chromosome 4q haplotype. In both forms of the disease, the mutations are associated with a partial relaxation of the D4Z4 chromatin structure and a failure to repress DUX4, a transcription factor normally expressed at high levels in germ cells of human testes, encoded by the D4Z4 unit in skeletal muscle.
The D4Z4 macrosatellite repeat is a polymorphic array consisting of 3.3kb D4Z4 units and is located in the subtelomere of chromosome 4q, at approximately 40kb distance to the telomere repeat. Due to a duplication event, a highly similar and equally polymorphic repeat array localizes to the subtelomere of chromosome 10q.
In the non-FSHD population, the size of the D4Z4 repeat array varies between 1–100 units on both chromosomes, except for FSHD permissive 4qA alleles (see below) where it varies between 11–100 units. At sizes >10 units it adopts a repressed chromatin structure in somatic cells as evidenced by high levels of CpG methylation and the presence of repressive histone modifications.
In patients diagnosed with FSHD1 the D4Z4 repeat array is contracted to 1–10 copies. In approximately half of the de novo cases (representing 10–30% of FSHD1), the contractions occurs somatically, most likely by an intrachromosomal gene conversion mechanism with or without cross over, and leading to somatic mosaicism for the disease allele. D4Z4 contractions to a size between 1–10 units are associated with partial relaxation of the D4Z4 chromatin structure in somatic cells (mostly determined by D4Z4 hypomethylation) and transcriptional derepression of the DUX4 retrogene in skeletal muscle,
The DUX4 retrogene in the D4Z4 repeat unit lacks its own polyadenylation signal but in the testis it makes use of a germline specific polyadenylation signal far distal to the D4Z4 repeat array.
DUX4 is a double-homeobox transcription factor that binds to a double-homeobox motif and regulates the expression of genes associated with stem cell and germline development. Mis-expression of DUX4 in skeletal muscle induces cell death and atrophic myotube formation, indicating that DUX4 expression is likely to be a major cause of the muscle pathology in FSHD. Furthermore, a large transcriptional deregulation that includes up-regulation of germline genes, genes required in stem cell biology as well as lncRNAs, and suppression of innate immune response genes has been reported in DUX4-transduced myoblasts as well as FSHD muscle.
There is a less common form of FSHD, and these individuals diagnosed with FSHD2 display clinical features that are identical to those observed in FSHD1 patients.
One of the most intriguing clinical observations in FSHD is the marked inter- and intrafamilial variability in disease onset and progression.
Early studies already suggested a rough and inverse relationship between D4Z4 repeat size and disease severity in FSHD1, with individuals carrying 1–3 units typically representing the most severe end of the disease spectrum.
In recent years major advances in our understanding of the molecular mechanisms underlying FSHD have been made. This has led to a model positioning DUX4 as a central player in FSHD pathophysiology. Also, the identification of SMCHD1, as the disease gene for FSHD2 and its role as a disease modifier in FSHD1, has highlighted that imbalances between genetic context and epigenetic regulation can crucially impact disease development.
Para mayor información acerca de esta patología, favor de ir al siguiente enlace: Genetic and epigenetic en FSHD
In families with the most frequent genetic cause of the disease (FSHD1), a contraction of the polymorphic D4Z4 macrosatellite repeat array on a specific FSHD-permissive haplotype of chromosome 4q, the disease segregates as a dominant trait.
In a small proportion of cases, the disease is caused by mutations in SMCHD1, a member of the condensin/cohesin family of chromatin compaction complexes that binds to the D4Z4 repeat array. In these FSHD2 families, the disease shows a more complex digenic inheritance because the mutation of SMCHD1 on chromosome 18 segregates independently from the FSHD-permissive chromosome 4q haplotype. In both forms of the disease, the mutations are associated with a partial relaxation of the D4Z4 chromatin structure and a failure to repress DUX4, a transcription factor normally expressed at high levels in germ cells of human testes, encoded by the D4Z4 unit in skeletal muscle.
The D4Z4 macrosatellite repeat is a polymorphic array consisting of 3.3kb D4Z4 units and is located in the subtelomere of chromosome 4q, at approximately 40kb distance to the telomere repeat. Due to a duplication event, a highly similar and equally polymorphic repeat array localizes to the subtelomere of chromosome 10q.
In the non-FSHD population, the size of the D4Z4 repeat array varies between 1–100 units on both chromosomes, except for FSHD permissive 4qA alleles (see below) where it varies between 11–100 units. At sizes >10 units it adopts a repressed chromatin structure in somatic cells as evidenced by high levels of CpG methylation and the presence of repressive histone modifications.
In patients diagnosed with FSHD1 the D4Z4 repeat array is contracted to 1–10 copies. In approximately half of the de novo cases (representing 10–30% of FSHD1), the contractions occurs somatically, most likely by an intrachromosomal gene conversion mechanism with or without cross over, and leading to somatic mosaicism for the disease allele. D4Z4 contractions to a size between 1–10 units are associated with partial relaxation of the D4Z4 chromatin structure in somatic cells (mostly determined by D4Z4 hypomethylation) and transcriptional derepression of the DUX4 retrogene in skeletal muscle,
The DUX4 retrogene in the D4Z4 repeat unit lacks its own polyadenylation signal but in the testis it makes use of a germline specific polyadenylation signal far distal to the D4Z4 repeat array.
DUX4 is a double-homeobox transcription factor that binds to a double-homeobox motif and regulates the expression of genes associated with stem cell and germline development. Mis-expression of DUX4 in skeletal muscle induces cell death and atrophic myotube formation, indicating that DUX4 expression is likely to be a major cause of the muscle pathology in FSHD. Furthermore, a large transcriptional deregulation that includes up-regulation of germline genes, genes required in stem cell biology as well as lncRNAs, and suppression of innate immune response genes has been reported in DUX4-transduced myoblasts as well as FSHD muscle.
There is a less common form of FSHD, and these individuals diagnosed with FSHD2 display clinical features that are identical to those observed in FSHD1 patients.
One of the most intriguing clinical observations in FSHD is the marked inter- and intrafamilial variability in disease onset and progression.
Early studies already suggested a rough and inverse relationship between D4Z4 repeat size and disease severity in FSHD1, with individuals carrying 1–3 units typically representing the most severe end of the disease spectrum.
In recent years major advances in our understanding of the molecular mechanisms underlying FSHD have been made. This has led to a model positioning DUX4 as a central player in FSHD pathophysiology. Also, the identification of SMCHD1, as the disease gene for FSHD2 and its role as a disease modifier in FSHD1, has highlighted that imbalances between genetic context and epigenetic regulation can crucially impact disease development.
Para mayor información acerca de esta patología, favor de ir al siguiente enlace: Genetic and epigenetic en FSHD
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