Novel sequence variations in LAMA2 and SGCG genes modulating cis-acting regulatory elements and RNA secondary structure

Siala, Olfa; Salem, Ikhlass Hadj; Tlili, Abdelaziz; Ammar, Imen Ben; Belguith, Hanen; Fakhfakh, Faiza

doi:10.1590/s1415-47572010005000008

Cited by 4 publications

(4 citation statements)

References 33 publications

(34 reference statements)

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“…Additionally, c.717 T and c.2242C > G variants were reported in Lebanese families presenting with mild and severe features respectively [48,49]. Novel polymorphisms in LAMA2 and SGCG, potentially influencing gene expression profiles, were identified in 35 healthy Lebanese individuals among other ethnicities [50].…”

Section: Limb Girdle Muscular Dystrophymentioning

confidence: 99%

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

Mégarbané

Bizzari

Deepthi

et al. 2022

JND

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Background: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. Objective: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. Methods: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999–2019) was reviewed. Results: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4%of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3%of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17%of patients). The latter disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5%of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. Conclusions: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

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Section: Limb Girdle Muscular Dystrophymentioning

confidence: 99%

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

Mégarbané

Bizzari

Deepthi

et al. 2022

JND

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“…Mutations that alter RNA secondary structures are known to be deleterious [33, 34]. They may cause structural changes in the coding mRNA transcripts, UTRs, tRNAs or rRNAs, which in turn may affect any of the gene processing steps, including transcription, splicing, translation and decay [33, 35–37].…”

Section: Disease Mutations That Alter Rna Secondary Structuresmentioning

confidence: 99%

“…They may cause structural changes in the coding mRNA transcripts, UTRs, tRNAs or rRNAs, which in turn may affect any of the gene processing steps, including transcription, splicing, translation and decay [33, 35–37]. A recent deep sequencing of RNase-generated fragments of human transcriptomes indicated that as many as 15% of single nucleotide variants alter local RNA secondary structures [38].…”

Section: Disease Mutations That Alter Rna Secondary Structuresmentioning

confidence: 99%

The effects of structure on pre-mRNA processing and stability

Soemedi

Cygan

Rhine

et al. 2017

Methods

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Pre-mRNA molecules can form a variety of structures, and both secondary and tertiary structures have important effects on processing, function and stability of these molecules. The prediction of RNA secondary structure is a challenging problem and various algorithms that use minimum free energy, maximum expected accuracy and comparative evolutionary based methods have been developed to predict secondary structures. However, these tools are not perfect, and this remains an active area of research. The secondary structure of pre-mRNA molecules can have an enhancing or inhibitory effect on pre-mRNA splicing. An example of enhancing structure can be found in a novel class of introns in zebrafish. About 10% of zebrafish genes contain a structured intron that forms a bridging hairpin that enforces correct splice site pairing. Negative examples of splicing include local structures around splice sites that decrease splicing efficiency and potentially cause mis-splicing leading to disease. Splicing mutations are a frequent cause of hereditary disease. The transcripts of disease genes are significantly more structured around the splice sites, and point mutations that increase the local structure often cause splicing disruptions. Post-splicing, RNA secondary structure can also affect the stability of the spliced intron and regulatory RNA interference pathway intermediates, such as pre-microRNAs. Additionally, RNA secondary structure has important roles in the innate immune defense against viruses. Finally, tertiary structure can also play a large role in pre-mRNA splicing. One example is the G-quadruplex structure, which, similar to secondary structure, can either enhance or inhibit splicing through mechanisms such as creating or obscuring RNA binding protein sites.

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“…For example, the mutations found in the Internal Ribosome Entry Sites (IRES) of the human p53 mRNA cause mostly local changes within the IRES, inhibiting the binding of trans ‐acting factors essential for translation [Grover et al, ]. Some disease‐associated SNPs also have been reported to cause local structural changes affecting gene expression [Hill and Reynolds, ; Siala et al, ]. Such localized changes, however, are not detectable with global measures of structural difference, in particular when long RNA sequences are under consideration.…”

Section: Introductionmentioning

confidence: 99%

RNA snp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNP s

et al. 2013

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Structural characteristics are essential for the functioning of many noncoding RNAs and cis-regulatory elements of mRNAs. SNPs may disrupt these structures, interfere with their molecular function, and hence cause a phenotypic effect. RNA folding algorithms can provide detailed insights into structural effects of SNPs. The global measures employed so far suffer from limited accuracy of folding programs on large RNAs and are computationally too demanding for genome-wide applications. Here, we present a strategy that focuses on the local regions of maximal structural change between mutant and wild-type. These local regions are approximated in a “screening mode” that is intended for genome-wide applications. Furthermore, localized regions are identified as those with maximal discrepancy. The mutation effects are quantified in terms of empirical P values. To this end, the RNAsnp software uses extensive precomputed tables of the distribution of SNP effects as function of length and GC content. RNAsnp thus achieves both a noise reduction and speed-up of several orders of magnitude over shuffling-based approaches. On a data set comprising 501 SNPs associated with human-inherited diseases, we predict 54 to have significant local structural effect in the untranslated region of mRNAs. RNAsnp is available at http://rth.dk/resources/rnasnp.

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Novel sequence variations in LAMA2 and SGCG genes modulating cis-acting regulatory elements and RNA secondary structure

Cited by 4 publications

References 33 publications

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

The effects of structure on pre-mRNA processing and stability

RNA snp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNP s

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