scholarly journals A Multistage Sequencing Strategy Pinpoints Many Novel and Candidate Disease Alleles for Orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism

2019 ◽  
Author(s):  
Peter Meinke ◽  
Alastair R. W. Kerr ◽  
Rafal Czapiewski ◽  
Jose I. de las Heras ◽  
Elizabeth Harris ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Plasma Membrane ◽  
Muscular Dystrophy ◽  
Muscular Dystrophies ◽  
Orphan Diseases ◽  
New Approach ◽  
Genome Wide ◽  
Sequencing Strategy ◽  
Strong Candidate ◽  
Altered Gene

AbstractLimitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.

Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function

2019 ◽  
Vol 29 (3) ◽  
pp. 407-417
Author(s):  
Mairéad Flynn ◽  
Laura Whitton ◽  
Gary Donohoe ◽  
Ciaran G Morrison ◽  
Derek W Morris
Keyword(s):  
Gene Regulation ◽  
Association Studies ◽  
Cell Signalling ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Phenotypic Analysis ◽  
Genome Wide ◽  
Dependent Cell ◽  
Altered Gene

Abstract Mutations in genes that encode centrosomal/ciliary proteins cause severe cognitive deficits, while common single-nucleotide polymorphisms in these genes are associated with schizophrenia (SZ) and cognition in genome-wide association studies. The role of these genes in neuropsychiatric disorders is unknown. The ciliopathy gene SDCCAG8 is associated with SZ and educational attainment (EA). Genome editing of SDCCAG8 caused defects in primary ciliogenesis and cilium-dependent cell signalling. Transcriptomic analysis of SDCCAG8-deficient cells identified differentially expressed genes that are enriched in neurodevelopmental processes such as generation of neurons and synapse organization. These processes are enriched for genes associated with SZ, human intelligence (IQ) and EA. Phenotypic analysis of SDCCAG8-deficent neuronal cells revealed impaired migration and neuronal differentiation. These data implicate ciliary signalling in the aetiology of SZ and cognitive dysfunction. We found that centrosomal/ciliary genes are enriched for association with IQ, suggesting altered gene regulation as a general model for neurodevelopmental impacts of centrosomal/ciliary genes.

scholarly journals Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

2021 ◽  
Vol 22 (10) ◽  
pp. 5276
Author(s):  
Coralie Croissant ◽  
Romain Carmeille ◽  
Charlotte Brévart ◽  
Anthony Bouter
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Genetic Disorders ◽  
Muscle Cells ◽  
Cell Types ◽  
Clinical Severity ◽  
Skeletal Muscle Cells ◽  
Muscular Dystrophies ◽  
Membrane Repair ◽  
Human Skeletal Muscle Cells

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

scholarly journals Epigenomic Analysis of RAD51 ChIP-seq Data Reveals cis-regulatory Elements Associated with Autophagy in Cancer Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2547
Author(s):  
Keunsoo Kang ◽  
Yoonjung Choi ◽  
Hyeonjin Moon ◽  
Chaelin You ◽  
Minjin Seo ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Homologous Recombination ◽  
Cell Lines ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Genome Wide ◽  
E Box ◽  
Autophagy Pathway ◽  
Mcf 7

RAD51 is a recombinase that plays a pivotal role in homologous recombination. Although the role of RAD51 in homologous recombination has been extensively studied, it is unclear whether RAD51 can be involved in gene regulation as a co-factor. In this study, we found evidence that RAD51 may contribute to the regulation of genes involved in the autophagy pathway with E-box proteins such as USF1, USF2, and/or MITF in GM12878, HepG2, K562, and MCF-7 cell lines. The canonical USF binding motif (CACGTG) was significantly identified at RAD51-bound cis-regulatory elements in all four cell lines. In addition, genome-wide USF1, USF2, and/or MITF-binding regions significantly coincided with the RAD51-associated cis-regulatory elements in the same cell line. Interestingly, the promoters of genes associated with the autophagy pathway, such as ATG3 and ATG5, were significantly occupied by RAD51 and regulated by RAD51 in HepG2 and MCF-7 cell lines. Taken together, these results unveiled a novel role of RAD51 and provided evidence that RAD51-associated cis-regulatory elements could possibly be involved in regulating autophagy-related genes with E-box binding proteins.

scholarly journals Genome-wide analysis of enhancer RNA in gene regulation across 12 mouse tissues

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Jen-Hao Cheng ◽  
David Zhi-Chao Pan ◽  
Zing Tsung-Yeh Tsai ◽  
Huai-Kuang Tsai
Keyword(s):  
Gene Regulation ◽  
Genome Wide Analysis ◽  
Enhancer Rna ◽  
Genome Wide ◽  
Mouse Tissues

A new approach for studying gene regulation by distant DNA elements in transgenic mice

1999 ◽  
Vol 59 (1) ◽  
pp. 33-39 ◽  
Author(s):  
L. B. Nielsen ◽  
S. P. A. McCormick ◽  
S. G. Young
Keyword(s):  
Gene Regulation ◽  
Transgenic Mice ◽  
New Approach ◽  
Dna Elements

Analysis of yield and oil from a series of canola breeding trials. Part II. Exploring variety by environment interaction using factor analysisThis article is one of a selection of papers from the conference “Exploiting Genome-wide Association in Oilseed Brassicas: a model for genetic improvement of major OECD crops for sustainable farming”.

Genome ◽  
2010 ◽  
Vol 53 (11) ◽  
pp. 1002-1016 ◽  
Author(s):  
B.R. Cullis ◽  
A.B. Smith ◽  
C.P. Beeck ◽  
W.A. Cowling
Keyword(s):  
Pedigree Information ◽  
Environment Interaction ◽  
Correlation Matrices ◽  
New Approach ◽  
Genome Wide ◽  
Selection Indices ◽  
New Varieties ◽  
Oilseed Brassicas ◽  
Analytic Models ◽  
Selection Of

Exploring and exploiting variety by environment (V × E) interaction is one of the major challenges facing plant breeders. In paper I of this series, we presented an approach to modelling V × E interaction in the analysis of complex multi-environment trials using factor analytic models. In this paper, we develop a range of statistical tools which explore V × E interaction in this context. These tools include graphical displays such as heat-maps of genetic correlation matrices as well as so-called E-scaled uniplots that are a more informative alternative to the classical biplot for large plant breeding multi-environment trials. We also present a new approach to prediction for multi-environment trials that include pedigree information. This approach allows meaningful selection indices to be formed either for potential new varieties or potential parents.

Cardiac magnetic resonance in patients with muscular dystrophies

2020 ◽  
pp. 204748732092305 ◽  
Author(s):  
Chrysanthos Grigoratos ◽  
Alberto Aimo ◽  
Andrea Barison ◽  
Vincenzo Castiglione ◽  
Giancarlo Todiere ◽  
...  
Keyword(s):  
Cardiac Magnetic Resonance ◽  
Magnetic Resonance ◽  
Muscular Dystrophy ◽  
Cardiac Involvement ◽  
Prognostic Significance ◽  
Standard Technique ◽  
Muscle Disease ◽  
Added Value ◽  
Muscular Dystrophies ◽  
Inherited Disorders

Muscular dystrophies are inherited disorders sharing similar clinical features and dystrophic changes on muscle biopsy. Duchenne muscular dystrophy is the most common inherited muscle disease of childhood, and Becker muscular dystrophy is a milder allelic variant with a slightly lower prevalence. Myotonic dystrophy is the most frequent form in adults. Cardiac magnetic resonance is the gold standard technique for the quantification of cardiac chamber volumes and function, and also enables a characterisation of myocardial tissue. Most cardiac magnetic resonance studies in the setting of muscular dystrophy were carried out at single centres, evaluated small numbers of patients and used widely heterogeneous protocols. Even more importantly, those studies analysed more or less extensively the patterns of cardiac involvement, but usually did not try to establish the added value of cardiac magnetic resonance to standard echocardiography, the evolution of cardiac disease over time and the prognostic significance of cardiac magnetic resonance findings. As a result, the large and heterogeneous amount of information on cardiac involvement in muscular dystrophies cannot easily be translated into recommendations on the optimal use of cardiac magnetic resonance. In this review, whose targets are cardiologists and neurologists who manage patients with muscular dystrophy, we try to summarise cardiac magnetic resonance findings in patients with muscular dystrophy, and the results of studies evaluating the role of cardiac magnetic resonance as a tool for diagnosis, risk stratification and follow-up. Finally, we provide some practical recommendations about the need and timing of cardiac magnetic resonance examination for the management of patients with muscular dystrophy.

scholarly journals SURPRISING GENOTYPE EXPRESSED AS A COMMON LIMB-GIRDLE MUSCULAR DYSTROPHY

2017 ◽  
Vol 16 (2) ◽  
pp. 71-73
Author(s):  
Liviu Cozma ◽  
◽  
Maria Barsevschi ◽  
Cristina Mitu ◽  
Alexandra Bastian ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Clinical Picture ◽  
Histopathological Examination ◽  
Muscular Dystrophies ◽  
Myofibrillar Myopathy ◽  
Homozygous Variant ◽  
Heterozygous Variant ◽  
High Degree

Limb-girdle muscular dystrophies (LGMDs) comprise a phenotypical spectrum of muscular dystrophies with a high degree of genotypical variability. We describe the case of a 56-year-old male with a history and clinical picture sugestive for LGMD with skeletal and cardiologic involvement. Histopathological examination shows a severe dystrophic picture and geneting testing revealed a unique never reported genotype association: a homozygous variant in the DES gene, associated with myofibrillar myopathy type 1 and LGMD2R, as well as a heterozygous variant in the CRYAB gene, associated with myofibrillar myopathy type 2, both of which could be responsible for the clinical picture.

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