CAG repeats

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Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset (occurring at a mean age of 40.2 years). The clinical manifestation of MJD is dependent on the presence of an expansion of the (CAG) n motif within exon 10 of the ATXN3 gene, located at 14q32.1. The variance in onset of MJD is only partially correlated (B50-80%) with the extension of the CAG tract in genomic DNA (gDNA). The main aim of this work was to determine whether there are discrepancies in the size of the (CAG) n tract between gDNA and mRNA, and to establish whether there is a better association between age at onset and repeat size at the mRNA level. We typed gDNA and cDNA samples for the (CAG) n tract totalizing 108 wild-type and 52 expanded ATXN3 alleles. In wild-type alleles no differences were found between gDNA and cDNA. In expanded alleles, the CAG repeat size in gDNA was not always directly transcribed into the mRNA; on average there were differences of +1 repeat at the cDNA level. The slight discrepancies obtained were insufficient to cause significant differences in the distribution of the expanded alleles, and therefore no improvement in onset variance explanation was obtained with mRNA.

La enfermedad de Huntington (HD, por sus siglas en inglés) es una enfermedad neurodegenerativa progresiva, con una prevalencia en la población caucásica de 10.6-13.7 casos por 100 000 habitantes. La prevalencia de la forma juvenil (<20 años de edad) es de 0.5-1 caso por 100 000 habitantes. Hay cuatro formas de presentación de la enfermedad, que dependen de la edad en la que inician los síntomas. La forma de inicio infantil (< 10 años de edad) es la menos frecuente (1-3% de los pacientes); además se asocia con un gran número de repeticiones de tripletes CAG (citosina-adenina-guanina) en el gen HTT. La enfermedad de Huntington juvenil es una variante poco frecuente que se caracteriza por trastornos motores, psiquiátricos y cognitivos un tanto distintos a la presentación del adulto, así como una progresión más severa. Al ser una enfermedad incurable su diagnóstico es crucial para dar un óptimo manejo interdisciplinario así como asesoramiento genético oportuno a los pacientes y fa...

Androgen receptor (AR) gene CAG polymorphisms may be associated with body shape, and are associated with certain breast and prostate cancers. In addition, body shape is associated with risk for a variety of diseases, including heart disease, diabetes, and certain forms of cancer. The CAG repeat in exon l of the AR gene was quantified using Perkin Elmer Applied Biosystems GeneScan analysis software in 96 and 59 healthy Caucasian men and women, respectively, who were over the age of 50 years. All participants had body measurements taken and donated a blood sample. Waist measurements included circumferences at the 1) umbilicus (wstumb), 2) top of the iliac crest (wstili), and 3) midpoint between the lowest rib and the iliac crest (wstwst). Waist-hip ratio (Wl-IR) was calculated using each corresponding waist measurement, respectively (WHRUMB, WHRILI, WHRWST). Mean repeat length was significantly different (p < 0.01) between men (22 ± 0.3 repeats) and women (23 ± 0.3 repeats). There ...

We demonstrate a significant association between longer CAG repeats in the hKCa3/KCNN3 calcium-activated potassium channel gene and schizophrenia in Israeli Ashkenazi Jews. We genotyped alleles from 84 Israeli Jewish patients with schizophrenia and from 102 matched controls. The overall allele frequency distribution is significantly different in patients vs controls (P = 0.00017, Wilcoxon Rank Sum test), with patients showing greater lengths of the CAG repeat. Northern blots reveal substantial levels of ෂ9 kb and ෂ13 kb hKCa3/KCNN3 transcripts in brain, striated muscle, spleen and lymph nodes. Within the brain, hKCa3/KCNN3 transcripts are most abundantly expressed in the substantia nigra, lesser amounts are detected in the basal ganglia, amygdala, hippocampus and subthalamic nuclei, while little is seen in the cerebral cortex, cerebellum and thalamus. In situ hybridization reveals abundant hKCa3/KCNN3 message localized within the substantia nigra and ventral tegmental area, and along the distributions of dopaminergic neurons from these regions into the nigrostriatal and mesolimbic pathways. FISH analysis shows that hKCa3/KCNN3 is located on chromosome 1q21.

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf7...

Huntington's disease is a fatal and devastating neurodegenerative genetic disorder for which there is currently no cure. It is characterized by Huntingtin protein's mRNA transcripts with 36 or more CAG repeats. Inhibiting the formation of pathological complexes between these expanded transcripts and target proteins may be a valuable strategy against the disease. Yet, the rational design of molecules specifically targeting the expanded CAG repeats is limited by the lack of structural information. Here, we use well-tempered metadynamics-based free energy calculations to investigate pose and affinity of two ligands targeting CAG repeats for which affinities have been previously measured. The first consists of two 4-guanidinophenyl rings linked by an ester group. It is the most potent ligand identified so far, with K d =60(30) nM. The second consists of a 4-phenyl dihydroimidazole and 4-1H-indole dihydroimidazole connected by a CC bond (K d =700(80) nM). Our calculations reproduce the experimental affinities and uncover the recognition pattern between ligands' and their RNA target. They also provide a molecular basis for the markedly different affinity of the two ligands for CAG repeats as observed experimentally. These findings may pave the way for a structure-based hit-tolead optimization to further improve ligand selectivity towards CAG repeat-containing mRNAs.

Background The aim of this study was to determine the frequency of intermediate alleles (IAs) in ATXN1, ATXN2 and HTT in patients with neurodegenerative diseases. Methods This is a multicentric study that included 1126 Alzheimer disease (AD) , 433 frontotemporal dementia (FTD) and 610 Parkinson´s disease (PD) patients. In all cohorts, we genotyped CAG repeats in ATXN1 and ATXN2 genes. Additionally, in FTD cohort we genotyped CAG repeats in HTT gene. Results In the overall FTD cohort, the frequency of HTT IAs was significantly higher in cases comparatively to controls (6.9% vs. 2.9%; p=0.007.; OR:2.45 (1.30-4.62). The frequency was even higher for c9orf72 expansion negative individuals (7.4% vs. 2.9%; p=0.

Background The aim of this study was to determine the frequency of intermediate alleles (IAs) in ATXN1, ATXN2 and HTT in patients with neurodegenerative diseases. Methods This is a multicentric study that included 1126 Alzheimer disease (AD) , 433 frontotemporal dementia (FTD) and 610 Parkinson´s disease (PD) patients. In all cohorts, we genotyped CAG repeats in ATXN1 and ATXN2 genes. Additionally, in FTD cohort we genotyped CAG repeats in HTT gene. Results In the overall FTD cohort, the frequency of HTT IAs was significantly higher in cases comparatively to controls (6.9% vs. 2.9%; p=0.007.; OR:2.45 (1.30-4.62). The frequency was even higher for c9orf72 expansion negative individuals (7.4% vs. 2.9%; p=0.

Huntington’s Disease (HD) is a late-onset and progressive neurodegenerative disease of the central nervous system with autosomal dominant inheritance. The prevalence of the disease is about 1/100 000 among individuals of European descent. The clinical symptoms of HD involve motor dysfunction, behavioural disturbances and cognitive decline. The pathology of HD is restricted to the brain, and the predominant neuropathological hallmark is selective loss of neurons within the striatum. The human HD gene (IT-15) was localized to chromosome 4p16.3 and consists of 67 exons spanning 180 kb of DNA. The mutation underlying disease is the expansion of the highly polymorphic CAG repeat tract in the first exon of the HD gene In fact, HD belongs to a group of disorders for which the causative mutation is the expansion of CAG repeats in the respective genes. A total of nine such conditions have been described so far, which are collectively described as “Polyglutamin e Diseases”. In HD, normal chro...

Huntington's Disease (HD) is a late-onset and progressive neurodegenerative disease of the central nervous system with autosomal dominant inheritance. The prevalence of the disease is about 1/100 000 among individuals of European descent. The clinical symptoms of HD involve motor dysfunction, behavioural disturbances and cognitive decline. The pathology of HD is restricted to the brain, and the predominant neuropathological hallmark is selective loss of neurons within the striatum. The human HD gene (IT-15) was localized to chromosome 4p16.3 and consists of 67 exons spanning 180 kb of DNA. The mutation underlying disease is the expansion of the highly polymorphic CAG repeat tract in the first exon of the HD gene In fact, HD belongs to a group of disorders for which the causative mutation is the expansion of CAG repeats in the respective genes. A total of nine such conditions have been described so far, which are collectively described as "Polyglutamin e Diseases". In ...

HuntingtonÕs Disease (HD) is a late-onset and progressive neurodegenerative disease of the central nervous system with autosomal dominant inheritance. The prevalence of the disease is about 1/100 000 among individuals of European descent. The clinical symptoms of HD involve motor dysfunction, behavioural disturbances and cognitive decline. The pathology of HD is restricted to the brain, and the predominant neuropathological hallmark is selective loss of neurons within the striatum. The human HD gene (IT-15) was localized to chromosome 4p16.3 and consists of 67 exons spanning 180 kb of DNA. The mutation underlying disease is the expansion of the highly polymorphic CAG repeat tract in the first exon of the HD gene In fact, HD belongs to a group of disorders for which the causative mutation is the expansion of CAG repeats in the respective genes. A total of nine such conditions have been described so far, which are collectively described as ÒPolyglutamine DiseasesÓ. In HD, normal chrom...

Huntington gene is located on chromosome 4p16.3 IT15 locus considered a major causative gene of Huntington disorder. HTT is a neurodegenerative disorder mutation in gene cause abnormal movements and psychiatric disturbances. HTT is inherited in an autosomal dominant manner with almost complete penetrance and till now, no research studies provide insight into HTT gene. Bioinformatics analysis includes transcription factors binding sites, phylogenetic studies with reference to various selected orthologs and syntenic relationship of HTT gene. Our study showed that in HTT gene majority of the portion is conserved among two orthologs chimpanzee and mouse in significance to human. These studies also revealed information about conservation of genes among different ortholog species and their evolutionary relationship.