Modeling Diseases of Noncoding Unstable Repeat Expansions Using Mutant Pluripotent Stem Cells

Overview

Journal World J Stem Cells

Publisher Baishideng Publishing Group

Date 2015 Jul 2

PMID 26131313

Citations 8

Authors

Shira Yanovsky-Dagan

Hagar Mor-Shaked

Rachel Eiges

Affiliations

Soon will be listed here.

Abstract

Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences (mostly microsatellites) that become unstable beyond a critical length when transmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells (diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.

Citing Articles

Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges.

Zhu L, Li S, Li X, Yin P Transl Neurodegener. 2023; 12(1):46.

PMID: 37730668 PMC: 10510301. DOI: 10.1186/s40035-023-00377-7.

Genome-wide screening for genes involved in the epigenetic basis of fragile X syndrome.

Vershkov D, Yilmaz A, Yanuka O, Nielsen A, Benvenisty N Stem Cell Reports. 2022; 17(5):1048-1058.

PMID: 35427485 PMC: 9133649. DOI: 10.1016/j.stemcr.2022.03.011.

Myotonic dystrophy type 1 (DM1) clinical subtypes and CTCF site methylation status flanking the CTG expansion are mutant allele length-dependent.

Morales F, Corrales E, Zhang B, Vasquez M, Santamaria-Ulloa C, Quesada H Hum Mol Genet. 2021; 31(2):262-274.

PMID: 34432028 PMC: 8831269. DOI: 10.1093/hmg/ddab243.

From Mouse Models to Human Disease: An Approach for Amyotrophic Lateral Sclerosis.

Alrafiah A In Vivo. 2018; 32(5):983-998.

PMID: 30150420 PMC: 6199613. DOI: 10.21873/invivo.11339.

Generation and Neuronal Differentiation of hiPSCs From Patients With Myotonic Dystrophy Type 2.

Spitalieri P, Talarico R, Murdocca M, Fontana L, Marcaurelio M, Campione E Front Physiol. 2018; 9:967.

PMID: 30100878 PMC: 6074094. DOI: 10.3389/fphys.2018.00967.

References

Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li H . Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013; 110(47):E4530-9. PMC: 3839752. DOI: 10.1073/pnas.1318835110. View

Jin P, Duan R, Qurashi A, Qin Y, Tian D, Rosser T . Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron. 2007; 55(4):556-64. PMC: 1994817. DOI: 10.1016/j.neuron.2007.07.020. View

TANEJA K, McCurrach M, Schalling M, Housman D, Singer R . Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol. 1995; 128(6):995-1002. PMC: 2120416. DOI: 10.1083/jcb.128.6.995. View

Lee G, Papapetrou E, Kim H, Chambers S, Tomishima M, Fasano C . Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature. 2009; 461(7262):402-6. PMC: 2784695. DOI: 10.1038/nature08320. View

Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson D . Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A. 2013; 110(19):7778-83. PMC: 3651485. DOI: 10.1073/pnas.1219643110. View

Rudnicki D, Holmes S, Lin M, Thornton C, Ross C, Margolis R . Huntington's disease--like 2 is associated with CUG repeat-containing RNA foci. Ann Neurol. 2007; 61(3):272-82. DOI: 10.1002/ana.21081. View

Pearson C, Tam M, Wang Y, Montgomery S, Dar A, Cleary J . Slipped-strand DNAs formed by long (CAG)*(CTG) repeats: slipped-out repeats and slip-out junctions. Nucleic Acids Res. 2002; 30(20):4534-47. PMC: 137136. DOI: 10.1093/nar/gkf572. View

Montermini L, Andermann E, Labuda M, Richter A, Pandolfo M, Cavalcanti F . The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. Hum Mol Genet. 1997; 6(8):1261-6. DOI: 10.1093/hmg/6.8.1261. View

Cleary J, Ranum L . Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet. 2013; 22(R1):R45-51. PMC: 3782068. DOI: 10.1093/hmg/ddt371. View

10.

Kanadia R, Shin J, Yuan Y, Beattie S, Wheeler T, Thornton C . Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc Natl Acad Sci U S A. 2006; 103(31):11748-53. PMC: 1544241. DOI: 10.1073/pnas.0604970103. View

11.

Miller J, Urbinati C, Stenberg M, Byrne B, Thornton C, Swanson M . Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 2000; 19(17):4439-48. PMC: 302046. DOI: 10.1093/emboj/19.17.4439. View

12.

Gore A, Li Z, Fung H, Young J, Agarwal S, Antosiewicz-Bourget J . Somatic coding mutations in human induced pluripotent stem cells. Nature. 2011; 471(7336):63-7. PMC: 3074107. DOI: 10.1038/nature09805. View

13.

Burman R, Popovich B, Jacky P, Turker M . Fully expanded FMR1 CGG repeats exhibit a length- and differentiation-dependent instability in cell hybrids that is independent of DNA methylation. Hum Mol Genet. 1999; 8(12):2293-302. DOI: 10.1093/hmg/8.12.2293. View

14.

Marteyn A, Maury Y, Gauthier M, Lecuyer C, Vernet R, Denis J . Mutant human embryonic stem cells reveal neurite and synapse formation defects in type 1 myotonic dystrophy. Cell Stem Cell. 2011; 8(4):434-44. DOI: 10.1016/j.stem.2011.02.004. View

15.

Colak D, Zaninovic N, Cohen M, Rosenwaks Z, Yang W, Gerhardt J . Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science. 2014; 343(6174):1002-5. PMC: 4357282. DOI: 10.1126/science.1245831. View

16.

Yang J, Cai J, Zhang Y, Wang X, Li W, Xu J . Induced pluripotent stem cells can be used to model the genomic imprinting disorder Prader-Willi syndrome. J Biol Chem. 2010; 285(51):40303-11. PMC: 3001010. DOI: 10.1074/jbc.M110.183392. View

17.

Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D . Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science. 2000; 289(5485):1769-73. DOI: 10.1126/science.289.5485.1769. View

18.

Bell A, West A, Felsenfeld G . The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999; 98(3):387-96. DOI: 10.1016/s0092-8674(00)81967-4. View

19.

Alisch R, Wang T, Chopra P, Visootsak J, Conneely K, Warren S . Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus. BMC Med Genet. 2013; 14:18. PMC: 3599197. DOI: 10.1186/1471-2350-14-18. View

20.

Urbach A, Bar-Nur O, Daley G, Benvenisty N . Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell. 2010; 6(5):407-11. PMC: 3354574. DOI: 10.1016/j.stem.2010.04.005. View