Induction of instability of normal length trinucleotide repeats within human disease genes (original) (raw)
Related papers
Origin and Expansion of Trinucleotide Repeats and Neurological Disorders
Current Genomics, 2005
Unstable expansions of trinucleotide repeats (TNRs) are associated with a growing number of neurological disorders (at least 14), including HD (Huntington's disease), fragile X-syndrome, MD (Myotonic dystrophy) and Freidreich's ataxia. These disorders are often characterized by a tendency of certain pathological alleles to further expand due to biases in the parental origin of mutations, at times, leading to the most severe forms. TNR expression involves changes in the repeat tract length, threshold value, secondary structure formation, interruptions, mismatch repair mechanism, genes and their involved sequences, the product thereof and anticipation. The interactions of each of these factors with the others influence manifestations of the disease. The exact cellular events and/or mechanism of varied expression in all the neurological diseases with similar repeats have not yet been clearly understood. A correlation between trinucleotide expansion, chromosomal fragile sites and neurological diseases has, however, been established. This review deals with the involvement of TNRs in neurological disorders with respect to the type of repeat, level of normal, premutation and expansion of repeats, chromosomal locus and the involved genes along with clinical implications. Possible answers to two basic questions regarding the mechanisms of involvement of repeat expansions and interrelationships between such expansions and fragile sites have been provided based on the available experimental data. Detection of trinucleotide repeat expansion and fragile genetic sites could be among the excellent parameters for screening and diagnosis of human neurodegenerative disorders. An insight into the mechanisms involved may help the clinicians to develop suitable treatments.
Trinucleotide expansion in disease: why is there a length threshold?
Current Opinion in Genetics & Development, 2014
Trinucleotide repeats (TNRs) expansion disorders are severe neurodegenerative and neuromuscular disorders that arise from inheriting a long tract (30-50 copies) of a trinucleotide unit within or near an expressed gene (Figure 1a). The mutation is referred to as 'trinucleotide expansion' since the number of triplet units in a mutated gene is greater than the number found in the normal gene. Expansion becomes obvious once the number of repeating units passes a critical threshold length, but what happens at the threshold to render the repeating tract unstable? Here we discuss DNA-dependent and RNAdependent models by which a particular DNA length permits a rapid transition to an unstable state.
Neurogenetics, Part I, 2018
More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease and eight other polyglutamine disorders including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (Fragile X Syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.
The complex pathology of trinucleotide repeats
Current Opinion in Cell Biology, 1997
The expansion of trinucleotide repeat sequences has now been shown to be the underlying cause of at least ten human disorders. Unifying features among these diseases include the unstable behavior of the triplet repeat during germline transmission when the length of the repeat exceeds a critical value. However, the trinucleotide repeat disorders can be divided into two distinct groups. Type I disorders involve the expansion of CAG repeats, which encode an expanded polyglutamine, inserted into the open-reading frame of a gene that is usually quite broadly expressed. Recently, mouse models for type I disorders have been developed and the basis of pathology is under study, both in these models and through biochemical and cell biological approaches. The type II disorders involve repeat expansions in noncoding regions of genes. The mechanisms by which these repeat expansions lead to pathology may be quite diverse.
Evolution of the Friedreich's ataxia trinucleotide repeat expansion: Founder effect and premutations
Proceedings of the National Academy of Sciences, 1997
Friedreich's ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for Ϸ17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through ''premutation'' intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.
Repeat instability: mechanisms of dynamic mutations
Nature Reviews Genetics, 2005
GENETIC ANTICIPATION A phenomenon in which disease severity increases and/or age of onset of disease decreases from one generation to the next. 'when' and 'where' will lead to a better understanding of 'how' repeat instability occurs. Germline instability. All TNR diseases involve mutations during parent-to-offspring transmission, implicating germline mutations in TNR instability (FIG. 2).