Anticipation (genetics)

About: Anticipation (genetics) is a research topic. Over the lifetime, 669 publications have been published within this topic receiving 21784 citations. The topic is also known as: Genetic Anticipation & Anticipation, Genetic.

Torsional stress promotes trinucleotidic expansion in spermatids.

Abstract: Trinucleotide repeats are involved in various neurodegenerative diseases and are highly unstable both in dividing or non-dividing cells. In Huntington disease (HD), the age of onset of symptoms is inversely correlated to the number of CAG repeats within exon 1 of the HTT gene. HD shows paternal anticipation as CAG repeats are increased during spermatogenesis. CAG expansion were indeed found to be generated during the chromatin remodeling in spermatids where most histones are evicted and replaced by protamines. This process involves striking change in DNA topology since free supercoils must be eliminated. Using an in vitro CAG repeat reporter assay and a highly active nuclear extracts from spermatids, we demonstrate that free negative supercoils result in CAG TNR expansion at a stabilized hairpin. We also suggest a possible role for protamines in promoting localized torsional stress and consequently TNR expansion. The transient increase in torsional stress during spermiogenesis may therefore provide an ideal context for the generation of such secondary DNA structures leading to the paternal anticipation of trinucleotidic diseases.

Unstable expansion of CAG repeat and molecular mechanism of neurodegeneration in SCA1

Abstract: SCA1 is caused by unstable expansion of CAG repeat in the coding region of a novel gene located on chromosome 6p23. Expansion up to 40-80 repeats develop the disorder, and the repeat length correlates with age at onset, rate of progression, or clinical severity. Expanded SCA1 allele is unstable during meiosis and mitosis, which is related to anticipation phenomenon and somatic mosaicism, respectively. SCA1 gene is expressed ubiquitously. In neurons, its transcript (ataxin-1) localizes mostly in nucleus. Ataxin-1 with expanded glutamine repeat is highly ubiquinated and forms aggregation within nucleus. These findings in clinical genetical, and cell biology are all common in other polyglutamine disorders, highly indicating that common molecular mechanisms underlie in these disorders. Based on these background, recent progress in the research for SCA1 is reviewed.

Novel mutational mechanism in man: Expansion of trinucleotide repeats

Abstract: An analysis of a novel, recently discovered class of mutations in man - an expansion, i.e., an increase of the copy number of intragenic unstable trinucleotide repeats - is presented. The expansion of trinucleotide X chromosome syndrome (two separate variants of the disease - FRAXA and FRAXE), myotonic dystrophy, spinal and bulbar Kennedy`s amyotrophy, Huntington`s chorea, type 1 spinocerebellar ataxia, and dentatorubral-pallidolyusian atrophy. The discovery of triplet expansion allows a satisfactory explanation on the molecular level of a series of unusual clinical genetic phenomena, such as anticipation, the {open_quotes}paternal transmission{close_quotes} effect, the {open_quotes}Sherman paradox,{close_quotes} and others. The common properties and the distinctions of unstable trinucleotide mutations in the nosologic forms mentioned above are analyzed comprehensively. These features include the mechanism by which these mutations cause disease, the time of their appearance in ontogenesis, and various clinical genetic correlations. The evolutionary origin of this class of mutations and, in particular, the role of alleles with an {open_quotes}intermediate{close_quotes} triplet number, which are the persistent reservoir of mutations arising de novo in a population, are also discussed. The possible implication of unstable trinucleotide repeats for a series of other hereditary diseases, such as type 2, spinocerebellar ataxia, Machado-Joseph disease, hereditary spastic paraplegia, essentialmore » tremor, schizophrenia, and others, is also suggested. 108 refs., 1 tab.« less

Dentatorubral pallidoluysian atrophy.

Abstract: Publisher Summary This chapter provides an insight of the epidemiology, clinical features, imaging, genetics, pathology, diagnosis, and treatment of dentatorubral pallidoluysian atrophy (DRPLA). Most reported DRPLA cases are from Japan. DRPLA is a trinucleotide CAG repeat disorder caused by expansion of the CTG-B37 gene on chromosome 12p. The gene product, atrophin-1, is found throughout the body and the brain. Clinical heterogeneity is the rule in DRPLA. The six dominant clinical features of DRPLA are: ataxia, chorea, dementia/mental retardation, epilepsy, myoclonus, and psychiatric/behavioral symptoms. Pathologically, there is atrophy of the dentatorubral and pallidoluysian systems. As with other CAG repeat disorders, NIIs and diffuse polyglutamine expression are noted throughout the brain. DRPLA has the largest expansion and the most prominent anticipation among CAG repeat disorders, with earlier and more severe disease with paternal inheritance. DRPLA may be divided according to onset age: juvenile-onset types (

Las mutaciones inestables, nuevo reto para el consejo genético de enfermedades hereditarias

Abstract: Unstable mutations or amplification of DNA tandem repeats sequences constitute a new kind of genetic alteration discovered in the 90´s that cause hereditary diseases. This mutation has been found inside or near important genes involved in the normal neurological function in human beings. In some cases, the presence of the amplification causes altered expression of the genes, their inactivation or the synthesis of a protein with new functions. Some common characteristics of these diseases are that they affect the central nervous system and are degenerative in nature. Most of them show genetic anticipation meaning that the severity of the manifestations increases in each generation and appear at an earlier age. In most cases, the severity of the symptoms is positively correlated with the size of the amplification. Twenty illnesses caused by this kind of mutations have been identified so far. Briefly, this work reviews the current knowledge about this topic.