Investigation of the Influence of TBP CAG/CAA Repeats in Conjunction with HTT CAG Repeats on Huntington's Disease Age at Onset in a Brazilian Sample.

Huntington's disease (HD) is a genetic neurodegenerative progressive and fatal disease characterized by motor disorder, cognitive impairment, and behavioral problems, caused by expanded repeats of CAG trinucleotides in the HTT gene. The aim of this study was to investigate the influence of TBP gene CAG/CAA repeats in conjunction with HTT gene CAG repeats, on the age at HD onset in Brazilian individuals. Individuals diagnosed as molecularly negative for HD presented 29-39 TBP CAG/CAA. Their most frequent allele had 36 repeats. In individuals diagnosed as molecularly positive for HD, a range of 25-40 TBP CAG/ CAA was found. The most frequent TBP allele had 38 repeats. We also conducted TBP direct Sanger sequencing of some samples which demonstrated other four TBP structures different from the basic TBP structure and others reported in the literature. The HTT expanded CAG and TBP CAG/CAA repeat sizes jointly explained 66% of the age at onset (AO) in our HD patients. The strongest variable in the model associated with AO was the number of expanded HTT CAG repeats. The difference between the association of HD AO with HTT expanded CAG together with TBP CAG/CAA and the association of HD AO with HTT expanded CAG was 0.001 (∆R2). Therefore, we found a weak association (0.1%) of TBP CAG/CAA repeats on HD AO, if any.

Neuromyelitis optica is an HLA associated disease different from Multiple Sclerosis: a systematic review with meta-analysis.

Neuromyelitis Optica and Multiple Sclerosis are idiopathic inflammatory demyelinating diseases of the central nervous system that currently are considered distinct autoimmune diseases, so differences in genetic susceptibility would be expected. This study aimed to investigate the HLA association with Neuromyelitis Optica by a systematic review with meta-analysis. The STROBE instrument guided research paper assessments. Thirteen papers published between 2009 and 2020 were eligible. 568 Neuromyelitis Optica patients, 41.4% Asians, 32.4% Latin Americans and 26.2% Europeans were analyzed. Only alleles of the DRB1 locus were genotyped in all studies. Neuromyelitis Optica patients have 2.46 more chances of having the DRB1*03 allelic group than controls. Ethnicity can influence genetic susceptibility. The main HLA association with Neuromyelitis Optica was the DRB1*03:01 allele in Western populations and with the DPB1*05:01 allele in Asia. Differences in the Multiple Sclerosis and Neuromyelitis Optica genetic susceptibility was confirmed in Afro descendants. The DRB1*03 allelic group associated with Neuromyelitis Optica has also been described in other systemic autoimmune diseases.

Author Correction: A systematic literature review on the European, African and Amerindian genetic ancestry components on Brazilian health outcomes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.

A systematic literature review on the European, African and Amerindian genetic ancestry components on Brazilian health outcomes.

The variables such as race, skin colour and ethnicity have become intensely discussed in medicine research, as a response to the rising debate over the importance of the ethnic-racial dimension in the scope of health-disease processes. The aim of this study was to identify the European (EUR), African (AFR) and Amerindian (AMR) ancestries on Brazilian health outcomes through a systematic literature review. This study was carried out by searching in three electronic databases, for studies published between 2005 and 2017. A total of 13 papers were eligible. The search identified the following health outcomes: visceral leishmaniosis, malaria, Alzheimer's disease, neuromyelitis optica, multiple sclerosis, prostate cancer, non-syndromic cleft lip/palate, chronic heart failure, sickle cell disease, primary congenital glaucoma, preterm labour, preterm premature rupture of membranes, systemic lupus erythematosus and type 1 diabetes mellitus. Research paper assessments were guided by the STROBE instrument, and agreements between results were determined by comparing the points attributed by two authors. Increased EUR ancestry was identified from preterm labour (PTL), type 1 diabetes (T1D) and non-syndromic cleft lip with or without cleft palate (NSCL), as well as in patients presenting aggressive prostate cancer prognoses. On the other hand, the highest AFR ancestral component was verified from systemic lupus erythematosus (SLE) and primary congenital glaucoma (PCG) cases, presenting worse prognoses. AMR ancestry may be a protective factor in the development of Alzheimer's disease (AD). The worst hemodynamic parameters in cases of heart failure (HF) were identified among individuals with greater AMR and AFR ancestry indices.

Avaliação funcional em indivíduos com doença de Huntington: uma série de casos / Functional evaluation in Huntington's disease: a series of cases

A doença de Huntington (DH) é uma desordem neurodegenerativa, que cursa com distúrbios motores, cognitivos e comportamentais que contribuem para o comprometimento da funcionalidade. Este estudo investigou o grau de funcionalidade e acometimento de indivíduos portadores da DH, com o Índice de Barthel Modificado (IBM) e por meio do Disease Burden Score (DBS). As variáveis analisadas de cada indivíduo foram: a idade atual, o gênero, a idade de início da doença e o número das repetições CAG (gene HTT). Seis indivíduos foram avaliados, três do sexo masculino 63,6 anos (±10,9) e três do sexo feminino 58,3 anos (±14,2) com o diagnóstico genético positivo para DH provenientes do município de Ervália/MG. O sexo feminino apresentou a idade de início menor comparado ao sexo masculino, com média de 38,3 anos (±8,9) e 46,6 anos (±7,6), respectivamente. O valor médio do número de repetições CAG no sexo feminino foi de 46,3 (±4,1) e no sexo masculino, 42,33 (±1,5). O grau de desempenho funcional determinado pelo IBM foi de 9,3 (±1,1) para o sexo feminino, com dependência total, e para o sexo masculino, 36 (±4,3), com dependência severa. O valor médio obtido pelo DBS no sexo feminino foi de 596,8 (±101,9), com maior grau de acometimento da doença comparado ao sexo masculino com 425,1 (±39,2). O grupo de mulheres com DH apresentou início dos sintomas mais cedo com maior número de expansões CAG quando comparado ao grupo masculino. Todos os pacientes apresentaram dependência total em relação à execução das atividades de vida diária. Sugere-se que pesquisas futuras sejam realizadas com maior número de indivíduos afetados pela DH para que os resultados observados sejam confirmados.

Huntington's disease (HD) is a neurodegenerative disorder, presenting with motor, cognitive and behavioral impairments that contribute to the decrease of the functional performance. This study investigated the degree of functionality and impairment of individuals with HD using the Modified Barthel Index (MBI) and the Disease Burden Score (DBS). The following variables were investigated : the age of onset, the gender, the current age and the number of CAG (HTT gene) repeats. Six HD patients from the municipality of Ervália-MG, three males 63.6 years old (±10.9) and three females 58.3 years old (±14.2), who had a positive genetic diagnosis for HD, were investigated. The female group had the lowest age of onset with an average of 38.3 years (±8.9), compared to the male group, with 46.6 years (±7.6). The mean of the number of CAG repeats in the female gender was 46.3 (±4.1) and in the male, 42.33 (±1.5). The degree of functional performance assessed by IBM was 9.3 (±1.1) for the female group, with total dependence, and for the male group, 36 (±4.3), with severe dependence. The mean of DBS value in the female group was 596.8 (±101.9) with a higher degree of disease involvement compared to the male group 425.1 (±39.2). The group of women with HD showed earlier onset of symptoms with a greater number of CAG repeats when compared to the male group. All patients presented total dependence on daily living activities. We strongly suggest further research involving a larger group of individuals affected by HD for statistical validation.

A Study of a Geographical Cluster of Huntington's Disease in a Brazilian Town of Zona da Mata, Minas Gerais State.

BACKGROUND/AIMS: Our aim was to investigate a geographical cluster of Huntington's disease (HD) in Ervalia, a Brazilian town of Minas Gerais state (MG). Therefore, we calculated the minimum prevalence of HD in Ervalia, known to have many HD affected families. We also determined the genetic profile of the polymorphic CAG region of the HTT gene in 32 subjects of these affected families. METHODS: A descriptive cross-sectional study was performed, starting in January 2011 until June 2013. Individuals who participated in the survey were all from Ervalia town, MG. RESULTS: The minimum prevalence rate found was 7.2/10,000 people, higher than the worldwide prevalence. CONCLUSION: The minimum prevalence of HD in Ervalia was at least 10.3- to 14.4-fold greater than that of the world population, although it does not represent the overall prevalence of the disease in Brazil. Certainly an expanded survey in the country will lead to a lower prevalence estimate than Ervalia's.

Actin immobilization on chitin for purifying myosin II: A laboratory exercise that integrates concepts of molecular cell biology and protein chemistry.

This article presents our experience on teaching biochemical sciences through an innovative approach that integrates concepts of molecular cell biology and protein chemistry. This original laboratory exercise is based on the preparation of an affinity chromatography column containing F-actin molecules immobilized on chitin particles for purifying skeletal myosin II. It favors the active learning of protein extraction and purification, the learning of concepts such as muscle contraction, cytoskeleton structure, and its importance for the living cell. This laboratory exercise also promotes learning biotechnological applications of chitin and the applications of protein immobilization in different industrial fields. Furthermore, the activities target the development of laboratorial abilities, problem-solving skills, and the ability to write a scientific report, following the model of a scientific article. The trials are mainly proposed for either an undergraduate project for advanced students in the life sciences or a postgraduate practical training course. In both the cases, the students must have had biochemistry as part of their regular curriculum. Alternatively, the affinity chromatography method can fit in any regular biochemistry course if active chitin, F-actin, and a myosin II extract are provided. It is very important to mention that this laboratory exercise can be used even in places where a facility such as ultracentrifugation is lacking. For that, the steps of actin purification are skipped, and actin is commercially obtained. Therefore, it is an adequate approach for the active learning of biochemical and molecular cell biology principles and techniques even in poor countries.