scholarly journals MicroRNA role in hereditary genetic diseases

2020 ◽  
pp. 5-17
Author(s):  
О.М. Плотникова ◽  
М.Ю. Скоблов
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Genetic Diseases ◽  
Hirschsprung Disease ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Diagnostic Methods ◽  
Hereditary Diseases ◽  
Beta Thalassemia ◽  
Genes Expression

На сегодняшний день известно около 7000 наследственных заболеваний. Однако современные методы ДНК диагностики выявляют причину возникновения заболеваний примерно в 40% случаев. Отчасти это обусловлено сложностью и большим разнообразием молекулярных механизмов их патогенеза. МикроРНК являются одним из мощнейших регуляторов экспрессии генов. Однако участие их в патогенезе наследственных заболеваний пока недостаточно изучено из-за сложностей поиска таких нарушений. В данной работе проведён анализ описанных механизмов патогенеза наследственных заболеваний, опосредованных нарушениями регуляции экспрессии генов посредством микроРНК. Такие случаи были выявлены при таких наследственных заболеваниях как муковисцидоз, миодистрофия Дюшенна, бета-талассемия, глаукома, лице-лопаточно-плечевая миодистрофия Ландузи-Дежерина, болезнь Гиршпрунга, синдром Ретта, синдром Туретта, пемфигус (болезнь Хейли-Хейли). To date, about 7,000 hereditary diseases are known. However, modern diagnostic methods reveal the cause of the disease in about 40% of cases. This is partly due to the complexity and wide variety of molecular mechanisms of pathogenesis. MicroRNAs are one of the most powerful genes expression regulators. But their participation in the pathogenesis of hereditary diseases has not yet been studied enough because of the difficulties in finding such disorders. In this work, we collected and analyzed pathogenesis of hereditary diseases mediated by dysregulation of gene expression by microRNA. such cases have been identified for such hereditary diseases as cystic fibrosis, Duchenne muscular dystrophy, beta-thalassemia, glaucoma, facioscapulohumeral muscular dystrophy Landouzy-Dejerine, Hirschsprung disease, Rett syndrome, Tourette syndrome, pemphigus (Hailey-Hailey disease).

scholarly journals Diagnosis of Duchenne/Becker muscular dystrophy and quantitative identification of carrier status by use of entangled solution capillary electrophoresis

1997 ◽  
Vol 43 (5) ◽  
pp. 745-751 ◽  
Author(s):  
Paolo Fortina ◽  
Jing Cheng ◽  
Mann A Shoffner ◽  
Saul Surrey ◽  
Wendy M Hitchcock ◽  
...  
Keyword(s):  
Capillary Electrophoresis ◽  
Muscular Dystrophy ◽  
Genetic Diseases ◽  
Becker Muscular Dystrophy ◽  
Diagnostic Methods ◽  
Carrier Status ◽  
Laser Induced Fluorescence Detection ◽  
General Utility ◽  
Pcr Products ◽  
Quantitative Results

Abstract Use of capillary electrophoresis, a new and useful analytical tool, offers a variety of advantages for nucleic acid analyses, including rapid analysis, automation, high resolution, qualitative and quantitative results, and low consumption of both sample and reagents. We report the first example of the use of entangled solution capillary electrophoresis (ESCE) and laser-induced fluorescence detection (LIF) for separation-based diagnostics in the quantitative analysis of multiplex PCR products for determination of carrier status of Duchenne/Becker muscular dystrophy (DMD/BMD). This ap-proach greatly improved the speed, resolution, and sensitivity of information needed for the diagnosis of DMD/BMD compared with that from conventional diagnostic methods, and is of general utility for diagnosis of genetic diseases.

scholarly journals Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (23) ◽  
pp. e2441-e2447 ◽  
Author(s):  
Kohei Hamanaka ◽  
Darina Šikrová ◽  
Satomi Mitsuhashi ◽  
Hiroki Masuda ◽  
Yukari Sekiguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Target Gene ◽  
Disease Gene ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Target Gene Expression ◽  
D4z4 Repeat ◽  
Biopsy Examination ◽  
Chromatin Relaxation

ObjectiveFacioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2.MethodsClinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies.ResultsA homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression.ConclusionLRIF1 is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate DUX4 expression in skeletal muscle.

scholarly journals Effective Classification and Gene Expression Profiling for the Facioscapulohumeral Muscular Dystrophy

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e82071 ◽  
Author(s):  
Félix F. González-Navarro ◽  
Lluís A. Belanche-Muñoz ◽  
Karen A. Silva-Colón
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Facioscapulohumeral Muscular Dystrophy

scholarly journals Cellular and molecular mechanisms underlying muscular dystrophy

2013 ◽  
Vol 201 (4) ◽  
pp. 499-510 ◽  
Author(s):  
Fedik Rahimov ◽  
Louis M. Kunkel
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Neuromuscular Disorders ◽  
Genetic Diseases ◽  
Model Systems ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Progressive Degeneration ◽  
Molecular Pathomechanisms

The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

scholarly journals New approach for diagnostic of Facioscapulohumeral muscular dystrophy based on PCR

2019 ◽  
pp. 3-9
Author(s):  
Н.В. Зернов ◽  
А.А. Гуськова ◽  
М.Ю. Скоблов
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Genetic ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Diagnostic Methods ◽  
Pulse Field ◽  
Agarose Gel ◽  
New Approach ◽  
Pulse Field Gel Electrophoresis ◽  
Pcr Products ◽  
The Moment

Актуальность. Миодистрофия Ландузи-Дежерина (МЛД) является одной из наиболее часто встречающихся мышечных дистрофий. В 95% случаев заболевание связано с частичной делецией массива повторов D4Z4 на одном из аллелей 4-й хромосомы. Существующие диагностические методики гибридизации по Саузерну и молекулярного комбинга являются ресурсо- и времязатратными. В настоящее время в Российской Федерации молекулярно-генетическая диагностика МЛД не проводится. Цель. Поиск новых подходов к диагностике МЛД для использования в молекулярно-генетических лабораториях. Методы. ДНК выделялась в агарозных блоках и подвергалась обработке эндонуклеазой EcoRI. Полученные фрагменты ДНК разделялись методом пульс-электрофореза в агарозном геле, после этого агарозный гель фрагментировался согласно маркеру молекулярного веса и использовался в качестве матрицы для полимеразной цепной реакции (ПЦР). Принадлежность полученных ПЦР-продуктов к последовательностям повторов D4Z4 4-й хромосомы подтверждалась секвенированием по Сэнгеру. Результаты. Протокол пульс-электрофореза оптимизирован таким образом, что после всех этапов ДНК в агарозном геле пригодна для использования в качестве матрицы для ПЦР. Разработана ПЦР-система специфичной амплификации контрольных ДНК-матриц 4-й хромосомы и подтверждена секвенированием принадлежность получаемых ПЦР-продуктов к последовательности повторов D4Z4 4-й хромосомы. Выводы. Показана возможность использования ДНК в агарозном геле после пульс-электрофореза в качестве матрицы для детекции повторов D4Z4 методом ПЦР. Представленная ПЦР-система специфично амплифицирует последовательности D4Z4 4-й хромосомы. Используя данную ПЦР-систему и геномную ДНК пациента с известной длиной массива повторов D4Z4 проведена успешная диагностика МЛД. Таким образом разработан новый подход к диагностике МЛД для использования в молекулярно-генетических лабораториях. Relevance. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. In 95% of cases, the disease is associated with partial deletion of the array of the D4Z4 repeats on one of the alleles of the 4th chromosome. The existing diagnostic methods of Southern blotting and molecular combing are quite resource-and time-consuming. At the moment, molecular genetic diagnostic of FSHD is not provided on the territory of the Russian Federation. Aim: to find new approaches for molecular genetic diagnostic of FSHD acceptable for use in standard molecular genetic laboratories Materials and methods: DNA isolated in agarose plugs and treated by the EcoRI restriction enzyme. DNA fragments then were separated by pulse field gel electrophoresis (PFGE) in agarose gel. After PFGE, the agarose gel was fragmented and used as a matrix for PCR. The identity of the obtained PCR products to the sequence of the D4Z4 repeats of the 4th chromosome was confirmed by sequencing by Sanger. Results. The PFGE protocol is optimized in such a way that, after all stages, DNA in agarose gel is suitable for use as a matrix for PCR. We achieve a specific amplification of the control DNA matrices of the 4th chromosome and confirm belonging of the PCR products to the sequence of D4Z4 repeats of the 4th chromosome by the Senger sequencing. Conclusions. This paper shows the possibility of using DNA in agarose gel after PFGE as a matrix for detection of D4Z4 repeats by PCR. The presented PCR system specifically amplify sequence of the 4th chromosome D4Z4 repeats. Using this PCR system and genomic DNA of a patient with a known length of the D4Z4 repeats array, a successful diagnosis of FSHD was performed. Thus, we propose a new approach for FSHD diagnostic, acceptable for use in standard molecular genetic laboratories.

scholarly journals Influence of Age and Immunostimulation on the Level of Toll-Like Receptor Gene (TLR3, 4, and 7) Expression in Foals

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1966
Author(s):  
Anna Migdał ◽  
Łukasz Migdał ◽  
Maria Oczkowicz ◽  
Adam Okólski ◽  
Anna Chełmońska-Soyta
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Receptor Gene ◽  
Venous Blood ◽  
Study Groups ◽  
Strong Negative Correlation ◽  
Genes Expression ◽  
Tlr4 Gene ◽  
Tlr3 Gene ◽  
Experimental Group

The aim of this study was to investigate the molecular mechanisms leading to the identification of pathogens by congenital immune receptors in foals up to 60 days of age. The study was conducted on 16 foal Polish Pony Horses (Polish Konik) divided into two study groups: control (n = 9) and experimental (n = 7). Foals from the experimental group received an intramuscular duplicate injection of 5 mL of Biotropina (Biowet) at 35 and 40 days of age. The RNA isolated from venous blood was used to evaluate the expression of theTLR3, TLR4, and TLR7 genes using RT-PCR. The results of the experiment demonstrated a statistically significant increase in the level of TLR3 gene expression and a decrease in the level ofTLR4 gene expression with foal aging. The level of TLR7 gene expression did not show age dependence. Immunostimulation with Biotropina had a significant impact on the level of the genes’ expression for Toll-like receptors. It increased the level of TLR4 expression and decreased TLR3 expression. Thus, it was concluded that the expression of theTLR3 and TLR4genes in peripheral blood cells is dependent on age. This experiment demonstrated a strong negative correlation between TLR3 and TLR4 gene expression.

scholarly journals Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy

2018 ◽  
Vol 28 (8) ◽  
pp. 1244-1259 ◽  
Author(s):  
Christopher R S Banerji ◽  
Maryna Panamarova ◽  
Johanna Pruller ◽  
Nicolas Figeac ◽  
Husam Hebaishi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Empirical Bayes ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Myogenic Differentiation ◽  
Critical Time ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Food Supplements ◽  
Biochanin A ◽  
Time Points

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic derepression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. For further analysis here, we selected pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), the cofactor and activator of oestrogen-related receptor α (ERRα). PGC1α knock-down caused hypotrophic myotubes to form from control myoblasts. Known ERRα agonists and safe food supplements biochanin A, daidzein or genistein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1α-ERRα axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily available food supplements.

scholarly journals β - catenin is central to DUX4 -driven network rewiring in facioscapulohumeral muscular dystrophy

2015 ◽  
Vol 12 (102) ◽  
pp. 20140797 ◽  
Author(s):  
Christopher R. S. Banerji ◽  
Paul Knopp ◽  
Louise A. Moyle ◽  
Simone Severini ◽  
Richard W. Orrell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Protein Interactions ◽  
Molecular Model ◽  
Meta Analysis ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Aberrant Expression ◽  
Incurable Disease ◽  
Therapeutic Development ◽  
Network Rewiring

Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring ( InSpiRe ), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe , we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4 , gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development.

scholarly journals The Role of ATP-binding Cassette Transporter Genes Expression for Treatment Failure in Cutaneous Leishmaniasis

2021 ◽  
Author(s):  
Mohammad Javad Boozhmehrani ◽  
Gilda Eslami ◽  
Ali Khamesipour ◽  
Abbas Ali Jafari ◽  
Mahmood Vakili
Keyword(s):  
Gene Expression ◽  
Treatment Failure ◽  
Cutaneous Leishmaniasis ◽  
Abc Transporter ◽  
Molecular Mechanisms ◽  
Atp Binding ◽  
Genes Expression ◽  
Abc Transporter Genes ◽  
Atp Binding Cassette

Abstract Background: Leishmaniasis is one of the common diseases transmitted by sand flies in tropical and subtropical regions of the world. Currently, antimonal derivatives are the first line of treatment. Some of the members of the ATP-binding cassette (ABC) family of Leishmania are shown to be associated with resistance to antimonial. In this study, we evaluated ABCI4, ABCG2, ABCC7, and ABCC3 gene expression in Leishmania isolated from patients with non-healing cutaneous leishmaniasis. Results: Five cases were treatment failure that all of them were identified as L. major. All treatment failure clinical isolates were L. major. Gene expression analysis in treatment failure isolates showed that the ABC transported genes had a different pattern in each isolate. ABCC7 had overexpression in all isolates. Among the treatment failure isolates, only one sample had overexpression in all ABC transporter genes under study. Conclusions: Treatment failure has been reported for cutaneous leishmaniasis worldwide. Knowledge of the molecular mechanisms of treatment failure could solve this problem. ABC transporter genes are considered controversy over the mechanisms of treatment failure outcomes. In this study, we showed that ABC transporter genes could be considered one the important mechanisms.

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