Tandem repeats in human disorders: mechanisms and evolution

Siwach, Pratibha

doi:10.2741/3017

Cited by 24 publications

(13 citation statements)

References 159 publications

(211 reference statements)

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“…A range of acquired diseases and inherited disorders are known to be associated with length mutations at tandem-repeat loci (Mirkin 2007;Usdin 2008;Siwash and Ganesh 2008). For example, an increased risk of breast, colon, bladder and ovarian cancer has been associated with the inheritance of rare alleles of a minisatellite Xanking the HRAS1 protooncogene.…”

Section: Who Cares About Heritable Mutations In Tandem-repeat Dna?mentioning

confidence: 99%

Air pollution and mutations in the germline: are humans at risk?

Somers

Cooper

2008

Hum Genet

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Genotoxic air pollution is ubiquitous in urban and industrial areas. A variety of studies has linked human exposure to air pollution with a number of different somatic cell endpoints including cancer. However, the potential for inducing mutations in the human germline remains unclear. Sentinel animal studies of germline mutations at tandem-repeat loci (specifically minisatellites and expanded simple tandem repeats) have recently provided proof of principle that germline mutations can be induced in vertebrates (birds and mice) by air pollution under ambient conditions. Although humans may also be susceptible to induced germline mutations in polluted areas, uncertainties regarding causative agents, doses, and mutational mechanisms at repetitive DNA loci currently preclude extrapolation from animal data to the evaluation of human risk. Nevertheless, several recent studies have linked air pollution exposure to DNA damage in human sperm, indicating that our germ cells are not impervious to the genotoxic effects of air pollution. Thus, both sentinel animal and human studies have raised the possibility that ambient air pollution may increase human germline mutation rates, especially at repetitive DNA loci. Given that some human genetic conditions appear to be modulated by length mutations at tandem-repeat loci (e.g. HRAS1 cancers, type 1 diabetes, etc.), there is an urgent need for extensive study in this area. Research should be primarily focused upon: (1) the direct measurement of mutation frequencies at repetitive DNA loci in human male germ cells as a function of air pollution exposure, (2) large-scale epidemiology studies of inherited disorders and tandem-repeat associated genetic conditions and air pollution, and (3) the characterization of mutational mechanisms at hypervariable tandem-repeat loci.

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Section: Who Cares About Heritable Mutations In Tandem-repeat Dna?mentioning

confidence: 99%

Air pollution and mutations in the germline: are humans at risk?

Somers

Cooper

2008

Hum Genet

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“…The best known example is Huntington’s disease where a sequence of more than 35–40 glutamines in the protein huntingtin, encoded by a CAG repeat in the corresponding gene, leads to the death of neurones [1,2]. Several other neurodegenerative diseases are similarly caused by CAG repeats coding for polyglutamine stretches in the respective genes [3,4]. Expansion of trinucleotide repeats coding for polyalanine have also been shown to be responsible for diseases [3,5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Several other neurodegenerative diseases are similarly caused by CAG repeats coding for polyglutamine stretches in the respective genes [3,4]. Expansion of trinucleotide repeats coding for polyalanine have also been shown to be responsible for diseases [3,5,6]. Remarkably, repeats of aspartic acid as short as five residues have been implicated in disease [7], indicating a functional role.…”

Section: Introductionmentioning

confidence: 99%

Single amino acid repeats in signal peptides

Łabaj¹,

Leparc²,

Bardet³

et al. 2010

The FEBS Journal

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There has been an increasing interest in single amino acid repeats ever since it was shown that these are the cause of a variety of diseases. Although a systematic study of single amino acid repeats is challenging, they have subsequently been implicated in a number of functional roles. In general surveys, leucine runs were among the most frequent. In the present study, we present a detailed investigation of repeats in signal peptides of secreted and type I membrane proteins in comparison with their mature parts. We focus on eukaryotic species because single amino acid repeats are generally rather rare in archaea and bacteria. Our analysis of over 100 species shows that repeats of leucine (but not of other hydrophobic amino acids) are over‐represented in signal peptides. This trend is most pronounced in higher eukaryotes, particularly in mammals. In the human proteome, although less than one‐fifth of all proteins have a signal peptide, approximately two‐thirds of all leucine repeats are located in these transient regions. Signal peptides are cleaved early from the growing polypeptide chain and then degraded rapidly. This may explain why leucine repeats, which can be toxic, are tolerated at such high frequencies. The substantial fraction of proteins affected by the strong enrichment of repeats in these transient segments highlights the bias that they can introduce for systematic analyses of protein sequences. In contrast to a general lack of conservation of single amino acid repeats, leucine repeats were found to be more conserved than the remaining signal peptide regions, indicating that they may have an as yet unknown functional role.

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“…The clinical features include spasticity and cognitive impairments. To date, ten such neurodegenerative disorders known to be caused by expansion of the CAG repeat in the coding region of the respective genes have been identified [21]. These prototypical protein misfolding disorders include Huntington disease (HD), six distinct forms of spinocerebellar ataxia (SCA-1, 2, 3, 6, 7 and 17), dentatorubropallidoluysian atrophy (DRPLA), and spinobulbar muscular atrophy (SBMA).…”

Section: Micrornas In Neurodegenerative Diseasesmentioning

confidence: 99%

Searching for MIND: MicroRNAs in Neurodegenerative Diseases

Barbato

Ruberti

Cogoni

2009

BioMed Research International

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In few years our understanding of microRNA (miRNA) biogenesis, molecular mechanisms by which miRNAs regulate gene expression, and the functional roles of miRNAs has been expanded. Interestingly, numerous miRNAs are expressed in a spatially and temporally controlled manner in the nervous system, suggesting that their posttrascriptional regulation may be particularly relevant in neural development and function. MiRNA studies in neurobiology showed their involvement in synaptic plasticity and brain diseases. In this review ,correlations between miRNA-mediated gene silencing and Alzheimer's, Parkinson's, and other neurodegenerative diseases will be discussed. Molecular and cellular neurobiological studies of the miRNAs in neurodegeneration represent the exploration of a new Frontier of miRNAs biology and the potential development of new diagnostic tests and genetic therapies for neurodegenerative diseases.

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Tandem repeats in human disorders: mechanisms and evolution

Cited by 24 publications

References 159 publications

Air pollution and mutations in the germline: are humans at risk?

Air pollution and mutations in the germline: are humans at risk?

Single amino acid repeats in signal peptides

Searching for MIND: MicroRNAs in Neurodegenerative Diseases

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