Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy

Miller, Jill W.; Urbinati, Carl R.; Teng-umnuay, Patana; Stenberg, Myrna G.; Byrne, Barry; Thornton, Charles A.; Swanson, Maurice S.

doi:10.1093/emboj/19.17.4439

Cited by 826 publications

(922 citation statements)

References 39 publications

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“…12 In other dominant intronic repeat disorders, such as Myotonic Dystrophy (DM1), these foci have been shown to sequester RNA-binding proteins, which cause a range of deleterious changes in RNA processing. 34,35 We propose that all C9ORF72 HREM cases derive from a single common founder and are now the most common cause of familial and sporadic ALS in Western Europe. The GGGGCC repeat is highly polymorphic and particularly unstable in the context of a specific haplotype (r), but the massive pathogenic expansion may have arisen on just one occasion around 6300 years ago.…”

Section: Human_reference : Gcgcgctaggggccggggccggggcc---------------mentioning

confidence: 99%

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

et al. 2012

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A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS þ / ÀFTD from five European cohorts (total n ¼ 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n ¼ 434) and controls (n ¼ 856). Haplotypes were analysed using PLINK and aged using DMLE þ . In a London clinic cohort, the HREM was the most common mutation in familial ALS þ / ÀFTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS þ / ÀFTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, Po10 À8 ). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

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Section: Human_reference : Gcgcgctaggggccggggccggggcc---------------mentioning

confidence: 99%

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

et al. 2012

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“…[2][3][4] At the molecular levels, the DM1 phenotype is most likely caused by a complex molecular pathogenesis, including deficiency of myotonic dystrophy myotonin kinase (DMPK) protein, [5][6][7] haplo-insufficiency of a neighboring homeobox gene (particular the DM locus-associated homeodomain protein (DMAHP/Six 5 gene) 8 and the WD-repeat gene (DMWD) 9 and a trans-dominant misregulation of RNA homeostasis. [10][11][12][13][14][15][16] Recent experiments from transgenic mice, expressing an untranslated expanded CUG repeat under the control of the human skeletal actin promoter, showed that expanded CUG repeats are sufficient to generate DM1 muscle phenotype. 17 These data suggest that misregulation of RNA homeostasis may play a major role in DM1 muscle pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Furling

Doucet²,

Ma³

et al. 2003

Gene Ther

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Myotonic dystrophy (DM1) is caused by the expansion of a trinucleotide repeat (CTG) located in the 3 0 untranslated region of the myotonic dystrophy protein kinase gene, for which currently there is no effective treatment. The data available suggest that misregulation of RNA homeostasis may play a major role in DM1 muscle pathogenesis. This indicates that the specific targeting of the mutant DMPK transcripts is essential to raise the rationale basis for the development of a specific gene therapy for DM1. We have produced a retrovirus which expresses a 149-bp antisense RNA complementary to the (CUG)13 repeats and to the 110-bp region following the repeats sequence to increase the specificity. This construct was introduced into human DM1 myoblasts, resulting in a preferential decrease in mutant DMPK transcripts, and effective restoration of human DM1 myoblast functions such as myoblast fusion and the uptake of glucose. It was previously shown that delay of muscle differentiation and insulin resistance in DM1 are associated with misregulation of CUGBP1 protein levels. The analysis of CUGBP1 levels and activity in DM1 cells expressing the antisense RNA indicated a correction of CUGBP1 expression in infected DM1 cells. We therefore show that current antisense RNA delivered in vitro using a retrovirus is not only capable of inhibiting mutant DMPK transcripts, but also can ameliorate dystrophic muscle pathology at the cellular levels. Gene Therapy (2003) 10, 795-802.

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“…12 In DM muscle, a downregulation of MBNL1 function and an upregulation of CELF1 function was shown. [15][16][17][18] For CELF1, multiple functions in RNA metabolism have been reported including regulation of alternative splicing, RNA stability and translational regulation of its RNA targets.…”

Section: Introductionmentioning

confidence: 96%

“…10 Both genetic types share a common pathomechanism: mutant mRNA transcripts containing CUG/CCUG expansions are retained in the nucleus and aggregate as nuclear foci. 11 RNA-binding proteins sequester in the nucleus, 12 resulting in mis-splicing of downstream effector genes (reviewed by Ranum and Cooper 13 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

et al. 2016

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The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG) n /(CCTG) n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica-protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBPassociated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) -associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction.

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Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy

Cited by 826 publications

References 39 publications

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

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