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Facioscapulohumeral muscular dystrophy: Are telomeres the end of the story?

Stadler G, King OD, Robin JD, Shay JW, Wright WE - Rare Dis (2013)

Bottom Line: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy with a relatively late age of onset (usually in the late teens) compared with Duchenne and many other muscular dystrophies.DUX4 mRNA is stable only when transcribed from certain haplotypes that contain a polyadenylation signal.We here put our data in the context of other recent findings arguing that progressive telomere shortening may play a critical role in FSHD but is not the whole story and that the current disease model needs additional refinement.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology; University of Texas Southwestern Medical Center; Dallas, TX USA.

ABSTRACT
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy with a relatively late age of onset (usually in the late teens) compared with Duchenne and many other muscular dystrophies. The current FSHD disease model postulates that contraction of the D4Z4 array at chromosome 4q35 leads to a more open chromatin conformation in that region and allows transcription of the DUX4 gene. DUX4 mRNA is stable only when transcribed from certain haplotypes that contain a polyadenylation signal. DUX4 protein is hypothesized to cause FSHD by mediating cytotoxicity and impairing skeletal muscle differentiation. We recently showed in a cell culture model that DUX4 expression is regulated by telomere length, suggesting that telomere shortening during aging may be partially responsible for the delayed onset and progressive nature of FSHD. We here put our data in the context of other recent findings arguing that progressive telomere shortening may play a critical role in FSHD but is not the whole story and that the current disease model needs additional refinement.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Possible mechanisms in FSHD. By itself, DUX4 expression from a contracted allele might not be sufficient to cause FSHD symptoms (A). Short telomeres would increase expression, but still might not be sufficient (B). A variety of additional factors could cooperate with DUX4 to increase muscle toxicity and produce weakness. A far from exhaustive list could include compound heterozygosity (having two contracted alleles, each increasing the dose of DUX4 expression so the total was sufficient to exceed a threshold, (C), and other conditions that compromised muscle function (such as a subclinical myopathy (D, E), or the increased expression of other factors that by themselves produced decreased muscle reserve but not overt symptoms: (F-H). Telomere length could modulate the age of onset and severity of symptoms by influencing DUX4 levels or the level of other genes.
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Figure 1: Figure 1. Possible mechanisms in FSHD. By itself, DUX4 expression from a contracted allele might not be sufficient to cause FSHD symptoms (A). Short telomeres would increase expression, but still might not be sufficient (B). A variety of additional factors could cooperate with DUX4 to increase muscle toxicity and produce weakness. A far from exhaustive list could include compound heterozygosity (having two contracted alleles, each increasing the dose of DUX4 expression so the total was sufficient to exceed a threshold, (C), and other conditions that compromised muscle function (such as a subclinical myopathy (D, E), or the increased expression of other factors that by themselves produced decreased muscle reserve but not overt symptoms: (F-H). Telomere length could modulate the age of onset and severity of symptoms by influencing DUX4 levels or the level of other genes.

Mentions: Besides genes at chromosome 4q, other loci may contribute to FSHD, such as CRYM, which has been found to be expressed at high levels in some FSHD families,9,11 and has functions putatively misregulated in FSHD. Noteworthy are numerous case reports about the co-occurrence of D4Z4 contraction and an independent myopathy.28-34Figure 1 summarizes some of the many possibilities in which short telomeres and other factors could cooperate in the production of FSHD symptoms.


Facioscapulohumeral muscular dystrophy: Are telomeres the end of the story?

Stadler G, King OD, Robin JD, Shay JW, Wright WE - Rare Dis (2013)

Figure 1. Possible mechanisms in FSHD. By itself, DUX4 expression from a contracted allele might not be sufficient to cause FSHD symptoms (A). Short telomeres would increase expression, but still might not be sufficient (B). A variety of additional factors could cooperate with DUX4 to increase muscle toxicity and produce weakness. A far from exhaustive list could include compound heterozygosity (having two contracted alleles, each increasing the dose of DUX4 expression so the total was sufficient to exceed a threshold, (C), and other conditions that compromised muscle function (such as a subclinical myopathy (D, E), or the increased expression of other factors that by themselves produced decreased muscle reserve but not overt symptoms: (F-H). Telomere length could modulate the age of onset and severity of symptoms by influencing DUX4 levels or the level of other genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927483&req=5

Figure 1: Figure 1. Possible mechanisms in FSHD. By itself, DUX4 expression from a contracted allele might not be sufficient to cause FSHD symptoms (A). Short telomeres would increase expression, but still might not be sufficient (B). A variety of additional factors could cooperate with DUX4 to increase muscle toxicity and produce weakness. A far from exhaustive list could include compound heterozygosity (having two contracted alleles, each increasing the dose of DUX4 expression so the total was sufficient to exceed a threshold, (C), and other conditions that compromised muscle function (such as a subclinical myopathy (D, E), or the increased expression of other factors that by themselves produced decreased muscle reserve but not overt symptoms: (F-H). Telomere length could modulate the age of onset and severity of symptoms by influencing DUX4 levels or the level of other genes.
Mentions: Besides genes at chromosome 4q, other loci may contribute to FSHD, such as CRYM, which has been found to be expressed at high levels in some FSHD families,9,11 and has functions putatively misregulated in FSHD. Noteworthy are numerous case reports about the co-occurrence of D4Z4 contraction and an independent myopathy.28-34Figure 1 summarizes some of the many possibilities in which short telomeres and other factors could cooperate in the production of FSHD symptoms.

Bottom Line: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy with a relatively late age of onset (usually in the late teens) compared with Duchenne and many other muscular dystrophies.DUX4 mRNA is stable only when transcribed from certain haplotypes that contain a polyadenylation signal.We here put our data in the context of other recent findings arguing that progressive telomere shortening may play a critical role in FSHD but is not the whole story and that the current disease model needs additional refinement.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology; University of Texas Southwestern Medical Center; Dallas, TX USA.

ABSTRACT
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy with a relatively late age of onset (usually in the late teens) compared with Duchenne and many other muscular dystrophies. The current FSHD disease model postulates that contraction of the D4Z4 array at chromosome 4q35 leads to a more open chromatin conformation in that region and allows transcription of the DUX4 gene. DUX4 mRNA is stable only when transcribed from certain haplotypes that contain a polyadenylation signal. DUX4 protein is hypothesized to cause FSHD by mediating cytotoxicity and impairing skeletal muscle differentiation. We recently showed in a cell culture model that DUX4 expression is regulated by telomere length, suggesting that telomere shortening during aging may be partially responsible for the delayed onset and progressive nature of FSHD. We here put our data in the context of other recent findings arguing that progressive telomere shortening may play a critical role in FSHD but is not the whole story and that the current disease model needs additional refinement.

No MeSH data available.


Related in: MedlinePlus