Article
Biochemistry & Molecular Biology
Joshua Paul Harvey, Patrick Yu-Wai-Man, Michael Edward Cheetham
Summary: Autosomal dominant optic atrophy (DOA) is a genetic optic neuropathy caused by OPA1 gene mutations. This study reports a novel splice variant in the OPA1 gene that leads to severe clinical manifestations and impaired mitochondrial function in a patient with DOA+.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Medicine, Research & Experimental
Audrey M. Winkelsas, Christopher Grunseich, George G. Harmison, Katarzyna Chwalenia, Carlo Rinaldi, Suzan M. Hammond, Kory Johnson, Melissa Bowerman, Sukrat Arya, Kevin Talbot, Matthew J. Wood, Kenneth H. Fischbeck
Summary: Research shows that ASOs targeting the 50 end of SMN2 can increase SMN mRNA and protein levels by inhibiting SMN2 mRNA decay. Combining 50 UTR ASO with SSO can elevate SMN levels beyond those achieved with SSO alone, offering a new therapeutic target for SMA.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2021)
Article
Multidisciplinary Sciences
Ruebena Dawes, Himanshu Joshi, Sandra T. Cooper
Summary: This study demonstrates a method for predicting cryptic donor activation caused by genetic splicing variants, with an empirical method defined by analyzing a large amount of RNA-Seq data, revealing the important determinants of cryptic donor activation.
NATURE COMMUNICATIONS
(2022)
Article
Cell & Tissue Engineering
Liani G. Devito, Fay Cooper, Ilenia D'Angelo, Jim Smith, Lyn Healy
Summary: This study generated four iPSC lines from patients with SMALED and characterized their pluripotency and differentiation potential. It revealed the crucial role of DYNC1H1 gene in the pathogenesis of SMALED.
STEM CELL RESEARCH
(2022)
Article
Plant Sciences
Weihua Huang, Liqun Zhang, Yajuan Zhu, Jingli Chen, Yawen Zhu, Fengru Lin, Xiaomei Chen, Jirong Huang
Summary: The usage of cryptic splice sites in plants remains unclear. In this study, two cryptic splicing regulators, RBP45d and PRP39a, were identified as homologs of yeast U1 auxiliary protein Nam8 and Prp39, respectively. It was found that RBP45d and PRP39a interact with each other and also with U1C, a core subunit of U1 snRNP, and promote U1 snRNP to recognize specific 5' splice sites by binding to intronic U-rich elements.
FRONTIERS IN PLANT SCIENCE
(2022)
Editorial Material
Genetics & Heredity
Eiichiro Amano, Tomokatsu Yoshida, Ikuko Mizuta, Jun Oyama, Shingo Sakashita, Syunsuke Ueyama, Akira Machida, Takanori Yokota
Summary: This case report describes an autopsied case of adult-onset Alexander disease with a novel splice site mutation. The patient presented mild upper motor neuron symptoms despite severe spinal cord and medulla oblongata atrophy. Genetic testing revealed a mutation in the canonical splice acceptor site, leading to activation of a cryptic splice acceptor site and expanding the clinical spectrum of ALXDRD.
NEUROLOGY-GENETICS
(2021)
Article
Endocrinology & Metabolism
Catarina I. I. Goncalves, Josianne N. N. Carrico, Omneya M. M. Omar, Ebtesam Abdalla, Manuel C. C. Lemos
Summary: HDR syndrome, caused by GATA3 gene mutations, is a rare autosomal dominant disorder characterized by hypoparathyroidism, deafness, and renal dysplasia. We report a case of an 11-year-old girl with HDR syndrome caused by a heterozygous mutation at the splice acceptor site of exon 5 of the GATA3 gene. Functional studies showed that this mutation led to abnormal splicing of GATA3 mRNA, resulting in the loss of a specific sequence from exon 5.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Review
Neurosciences
Brunhilde Wirth
Summary: The review highlights the challenging journey from gene discovery to therapy in spinal muscular atrophy (SMA), emphasizing the importance of perseverance in uncovering the biological mechanisms of the disease. Despite the impressive improvements seen with three therapeutic strategies in SMA, there are still many unanswered questions that need to be addressed as discussed in the review.
TRENDS IN NEUROSCIENCES
(2021)
Article
Chemistry, Analytical
Zhiqing Hu, Miaomiao Chen, Chunhua Zhang, Zhuo Li, Mai Feng, Lingqian Wu, Miaojin Zhou, Desheng Liang
Summary: Spinal muscular atrophy (SMA) is a major genetic cause of infant death. Researchers have developed a novel nucleic acid diagnostic method combining CRISPR/Cas14a1 and asymmetric PCR, which can specifically and sensitively detect the deletion of exon 7 of the SMN1 gene in SMA patients. The method has been validated in clinical samples and showed consistent results with other detection methods, demonstrating its potential as an accurate detection platform for genetic diseases and pathogens.
Article
Clinical Neurology
Crystal M. Proud, Eugenio Mercuri, Richard S. Finkel, Janbernd Kirschner, Darryl C. De Vivo, Francesco Muntoni, Kayoko Saito, Eduardo F. Tizzano, Isabelle Desguerre, Susana Quijano-Roy, Kamal Benguerba, Dheeraj Raju, Eric Faulkner, Laurent Servais
Summary: This study aimed to devise a rational and systematic approach for defining and grouping disease-modifying treatment scenarios for survival motor neuron-targeted diseases. The proposed classification, based on initial and subsequent treatment differentiation, was validated by applying it to the patients in the RESTORE registry.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
Article
Genetics & Heredity
Niall P. Keegan, Steve D. Wilton, Sue Fletcher
Summary: Understanding pre-mRNA splicing is crucial for diagnosing and treating genetic diseases. Pseudoexon mutations, which create new exons within introns, are rare and difficult to predict. Deep-intronic single nucleotide variants are a common cause of pseudoexons, suggesting that certain regions involved in splicing processes may be more susceptible to exonization. A comprehensive study of pseudoexon splice events can improve genetic diagnostics and reveal new targets for splice-modulating therapies.
FRONTIERS IN GENETICS
(2022)
Review
Genetics & Heredity
Jan Lejman, Grzegorz Zielinski, Piotr Gawda, Monika Lejman
Summary: Alternative splicing is a crucial mechanism that increases genetic diversity and can be a therapeutic target. Spinal Muscular Atrophy (SMA) is a neurodegenerative disease mainly caused by the homozygous deletion in the SMN1 gene, with 95% of cases attributed to this mutation.
Article
Clinical Neurology
Laura E. Habets, Bart Bartels, Fay-Lynn Asselman, Melissa T. Hooijmans, Sandra van den Berg, Aart J. Nederveen, W. Ludo van der Pol, Jeroen A. L. Jeneson
Summary: This study provides clinical evidence of abnormal muscle bioenergetics in patients with hereditary proximal spinal muscular atrophy, suggesting a potential role of mitochondrial dysfunction in the disease pathogenesis. The study also highlights the contribution of degeneration and atrophy of motor neurons and associated musculature, as well as the depletion of specific myofiber types, to muscle weakness in this cohort. These findings contribute to a better understanding of the underlying mechanisms of the disease and provide potential new biomarkers and targets for therapy.
Review
Clinical Neurology
Katarzyna Kotulska, Aviva Fattal-Valevski, Jana Haberlova
Summary: Spinal muscular atrophy is a neuromuscular disease caused by mutation of the SMN1 gene, but disease modifying therapies have shown effectiveness in improving motor functions of patients with SMA.
FRONTIERS IN NEUROLOGY
(2021)
Article
Medicine, Research & Experimental
Dian Marta Sari, Vitriana Biben, Guswan Wiwaha, Dany Hilmanto
Summary: This study aimed to assess the characteristics of SMA patients in the Indonesian SMA Community, evaluate the association between SMA type and delayed diagnosis, and analyze the risk of spinal deformities. The results showed that SMA type 2 patients had a two-fold risk of spinal deformities, delayed diagnosis was more common in SMA type 3, and the time interval between suspicion and definite diagnosis of SMA was associated with the risk of spinal deformities.
EUROPEAN JOURNAL OF MEDICAL RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
N. N. Singh, M. D. Howell, E. J. Androphy, R. N. Singh
Article
Biochemistry & Molecular Biology
Eric W. Ottesen, Natalia N. Singh, Diou Luo, Ravindra N. Singh
NUCLEIC ACIDS RESEARCH
(2018)
Article
Biochemistry & Molecular Biology
Eric W. Ottesen, Diou Luo, Joonbae Seo, Natalia N. Singh, Ravindra N. Singh
NUCLEIC ACIDS RESEARCH
(2019)
Review
Biochemistry & Molecular Biology
Ravindra N. Singh, Natalia N. Singh
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2019)
Article
Biochemistry & Molecular Biology
Natalia N. Singh, Ravindra N. Singh
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2019)
Editorial Material
Biochemistry & Molecular Biology
Francisco E. Baralle, Ravindra N. Singh, Stefan Stamm
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2019)
Editorial Material
Chemistry, Medicinal
Ravindra N. Singh
FUTURE MEDICINAL CHEMISTRY
(2019)
Review
Biochemistry & Molecular Biology
Natalia N. Singh, Eric W. Ottesen, Ravindra N. Singh
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2020)
Review
Pharmacology & Pharmacy
Ravindra N. Singh, Joonbae Seo, Natalia N. Singh
EXPERT OPINION ON THERAPEUTIC TARGETS
(2020)
Review
Cell Biology
Eric W. Ottesen, Ravindra N. Singh
CELLULAR SIGNALLING
(2020)
Article
Biochemistry & Molecular Biology
Natalia N. Singh, Shaine Hoffman, Prabhakara P. Reddi, Ravindra N. Singh
Summary: Spinal muscular atrophy (SMA) is a major genetic disorder associated with infant mortality, primarily caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. The spectrum of SMA ranges from prenatal death to survival into adulthood, with all tissues potentially affected.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Eric William Ottesen, Diou Luo, Natalia Nikolaevna Singh, Ravindra Narayan Singh
Summary: The intronic splicing silencer N1 (ISS-N1) within Survival Motor Neuron 2 (SMN2) intron 7 is a therapeutic target for treating spinal muscular atrophy. Treatment with 100 nM of Anti-N1 resulted in substantial stimulation of SMN2 exon 7 inclusion but also caused significant perturbations in the transcriptome and widespread aberrant splicing. Shorter ISS-N1-targeting ASOs showed a substantial reduction in off-target effects, providing important insights for better ASO design and dosing regimens of ASO-based drugs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
Diou Luo, Natalia Nikolaevna Singh, Ravindra Narayan Singh
Summary: This study investigates the generation mechanism of circRNA in SMN genes. It finds that the presence of introns enhances the rate of circRNA generation and that the exon junction complex plays a role in the generation of circRNAs containing only exons. In addition, SMN circRNAs are preferentially localized in the cytoplasm.
Article
Biochemistry & Molecular Biology
Eric W. Ottesen, Natalia N. Singh, Diou Luo, Bailey Kaas, Benjamin J. Gillette, Joonbae Seo, Hannah J. Jorgensen, Ravindra N. Singh
Summary: Designing an RNA-interacting molecule that exhibits both high therapeutic efficacy and concentration-specific specificity remains challenging. Risdiplam and branaplam, two small molecules approved for the treatment of spinal muscular atrophy (SMA) and undergoing clinical trials, respectively, are able to restore the inclusion of Survival Motor Neuron 2 (SMN2) exon 7. However, the transcriptome-wide off-target effects of these compounds in SMA patient cells reveal concentration-dependent changes and perturbations in gene expression, splicing events, and cellular pathways. Understanding these off-target effects and their mechanisms can guide the development of improved dosing regimens and future small molecule therapeutics for splicing modulation.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Neurosciences
Ravindra N. Singh, Eric W. Ottesen, Natalia N. Singh
NEUROSCIENCE INSIGHTS
(2020)