Contractions of D4Z4 on 4qB Subtelomeres Do Not Cause Facioscapulohumeral Muscular Dystrophy

Lemmers, Richard J F L; Wohlgemuth, M.; Frants, Rune R.; Padberg, George W.; Morava, Éva; Maarel, Silvère M. van der

doi:10.1086/426035

Cited by 109 publications

(80 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Deletions of the D4Z4 array give rise to FSHD only when they occur on the 4qA form (Lemmers et al 2002(Lemmers et al , 2004(Lemmers et al , 2007. Our chimpanzee 4q sequence surrounding the D4Z4 array confirms the proposal made by van Geel et al (2002a) that the human 4qA allele is ancestral to the 4qB allele.…”

Section: Post-speciation Sequence Exchange Among Paralogssupporting

confidence: 80%

Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event

Rudd

Endicott²,

Friedman³

et al. 2008

Genome Res.

View full text Add to dashboard Cite

Subtelomeres are concentrations of interchromosomal segmental duplications capped by telomeric repeats at the ends of chromosomes. The nature of the segments shared by different sets of human subtelomeres reflects their high rate of recent interchromosomal exchange. Here, we characterize the rearrangements incurred by the 15q subtelomere after it arose from a chromosome fission event in the common ancestor of great apes. We used FISH, sequencing of genomic clones, and PCR to map the breakpoint of this fission and track the fate of flanking sequence in human, chimpanzee, gorilla, orangutan, and macaque genomes. The ancestral locus, a cluster of olfactory receptor (OR) genes, lies internally on macaque chromosome 7. Sequence originating from this fission site is split between the terminus of 15q and the pericentromere of 14q in the great apes. Numerous structural rearrangements, including interstitial deletions and transfers of material to or from other subtelomeres, occurred subsequent to the fission, such that each species has a unique 15q structure and unique collection of ORs derived from the fission locus. The most striking rearrangement involved transfer of at least 200 kb from the fission-site region to the end of chromosome 4q, where much still resides in chimpanzee and gorilla, but not in human. This gross structural difference places the subtelomeric defect underlying facioscapulohumeral muscular dystrophy (FSHD) much closer to the telomere in human 4q than in the hybrid 4q-15q subtelomere of chimpanzee.[Supplemental material is available online at www.genome.org. The sequence data from this study have been submitted to GenBank under accession nos. AC188481, AC183330, AC150715, AC149242, AC148620, AC148535, AC173434, AC186245, AC205763, AC150448, AC183669, AC197422.]Subtelomeres are composed of interchromosomally duplicated sequences situated near the ends of chromosomes just proximal of telomeric repeats (Mefford and Trask 2002). Roughly half of the subtelomeric sequence in the human genome has moved or changed copy number since human and chimpanzee diverged (Linardopoulou et al. 2005). Due to this recent change, most subtelomeric duplications show variation in chromosomal location and copy number in the human population. Assays of the content of subtelomeres in other primates by fluorescence in situ hybridization (FISH) have revealed significant differences among species (Kingsley et al. 1997;Trask et al. 1998;Martin et al. 2002;van Geel et al. 2002b;Linardopoulou et al. 2005). However, no study has yet traced the evolution of a given subtelomere in primates by comparative analyses at the sequence level.The evolution of subtelomeres is "reticulate" (Jackson et al. 2005;Huson and Bryant 2006). Recurrent shuffling of material among ends makes it difficult to distinguish structures that are identical by descent from the shared presence (or absence) of particular sequences. Gene conversion-like transfers between duplicated segments can obfuscate the timing of the original duplication. In order to reconstru...

show abstract

Section: Post-speciation Sequence Exchange Among Paralogssupporting

confidence: 80%

Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event

Rudd

Endicott²,

Friedman³

et al. 2008

Genome Res.

View full text Add to dashboard Cite

show abstract

“…The 4qA161 haplotype is the most prevalent A haplotype in the Caucasian population and can be observed in ~39% of control individuals [17] . Thus far, only contractions in the 4qA161 haplotype have been shown to cause FSHD, while contractions in other 4q haplotypes such as 4qA166 and 4qB163 are non-pathogenic [17][18][19] ). Therefore, it is hypothesized that haplotype-specific sequence polymorphisms are mechanistically linked to FSHD pathogenesis [17] .…”

Section: Introductionmentioning

confidence: 99%

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

et al. 2009

Self Cite

View full text Add to dashboard Cite

Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date however, the methylation status of contracted repeats on non-pathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4-restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a non-pathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In fifteen FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD; (1) contraction-dependent or (2) contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere.

show abstract

“…12 -14 Contraction of D4Z4 is necessary but not sufficient to cause FSHD. 15 At least 9 different haplotypes of 4qter…”

Section: Introductionmentioning

confidence: 99%

Comprehensive expression analysis of FSHD candidate genes at the mRNA and protein level

et al. 2009

View full text Add to dashboard Cite

In facioscapulohumeral muscular dystrophy (FSHD) the majority of patients carry a D4Z4 macrosatellite repeat contraction in the subtelomere of chromosome 4q. Several disease mechanisms have been proposed to explain how repeat contraction causes muscular dystrophy. All proposed mechanisms foresee a change from a closed to a more open chromatin structure followed by loss of control over expression of genes in or proximal to D4Z4. Initially, a distance and residual repeat size-dependent upregulation of the candidate genes FRG2, FRG1 and ANT1 was observed, but most successive expression studies failed to support transcriptional upregulation of 4qter genes. Moreover, chromatin studies do not provide evidence for a cis-spreading mechanism operating at 4qter in FSHD. In part, this inconsistency may be explained by differences in the techniques used, and the use of RNA samples obtained from different muscle groups. The aim of this study is to comprehensively and uniformly study the expression of the FSHD candidate genes FRG1, FRG2, CRYM, ANT1, ALP, PITX1 and LRP2BP at the RNA and protein level in identically processed primary myoblasts, myotubes and quadriceps muscle. Expression was compared between samples obtained from FSHD patients and normal controls with samples from myotonic dystrophy type 1 patients as disease controls. No consistent changes in RNA or protein expression levels were observed between the samples. The one exception was a selective increase in FRG2 mRNA expression in FSHD myotubes. This study provides further evidence that there is no demonstrable consistent, large magnitude, overexpression of any of the FSHD candidate genes.

show abstract

Contractions of D4Z4 on 4qB Subtelomeres Do Not Cause Facioscapulohumeral Muscular Dystrophy

Cited by 109 publications

References 39 publications

Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event

Comparative sequence analysis of primate subtelomeres originating from a chromosome fission event

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

Comprehensive expression analysis of FSHD candidate genes at the mRNA and protein level

Contact Info

Product

Resources

About