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Spinal Cord Disease
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
SMA is a class of inherited diseases characterized by progressive degeneration of anterior horn cells and subsequent muscular atrophy and paralysis. For disease linked to the survival of motor neuron (SMN) gene: Incidence: infantile and juvenile SMA: 1 per 6000 newborns.Incidence of gene carrier status: 1–2% of population.Age: onset varies from birth to adulthood.
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
Regarding the RNA components of the SPL, mutations of U1 and U2 snRNA are implicated in cancer (hepatocellular carcinoma, CCL, and medulloblastoma). These mutations are responsible for 5’ cryptic splicing and intron retention events. Additionally, mutations of U1 snRNA at the 5’SS induce spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease and the leading genetic cause of newborn lethality [26,27,71–73]. The mechanism underlying SMA onset is rather complex. SMA is caused by a homozygous deletion of the survival of motor neuron-1 gene (SMN1) in chromosome 5 encoding for the SMN protein, which plays a critical role in snRNP assembly [72–74]. In humans, two paralog SMN genes exist: SMN1 and SMN2 [75]. The SMN protein produced by the SMN2 gene cannot fully compensate for the loss of SMN1 in SMA patients.
Unfolding the Role of Splicing Factors and RNA Debranching in AID Mediated Antibody Diversification
Published in International Reviews of Immunology, 2021
Ankit Jaiswal, Amit Kumar Singh, Anubhav Tamrakar, Prashant Kodgire
CTNNBL1 being a part of CDC5L and Prp19 complex [89] that is localized in the Cajal body (CB), so is it possible that AID and CTNNBL1 were also present in the CB. Thus, it is worth exploring that if AID and CTNNBL1 are localized in the CB, and if they are localized, do they interact with the CB associated proteins. CB is the structure present in the nucleus that is the home to snRNPs and splicing factors. Survival of Motor Neuron (SMN) protein and coilin protein are the most abundant proteins found in the CB. Subsequent experiments confirmed that CTNNBL1 and AID are localized with CB associated proteins SMN in live HeLa cells, as well as fixed cells. Additionally, CTNNBL1 and AID were found to interact with CB associated proteins SMN as well as coilin as demonstrated by CoIP experiments. Interestingly, AID 1-81 amino acids are indispensable for its localization to the CB [70]. Moreover, AID localization to the CB is independent of its interaction with CTNNBL1. Finally, it can be concluded that AID and CTNNBL1 are localized at the CB as well as interact with CB associated proteins [70].
Is there hope for spinal muscular atrophy synthetic pharmacotherapy?
Published in Expert Opinion on Pharmacotherapy, 2019
Proximal spinal muscular atrophy (SMA) is a neurodegenerative disorder and the leading genetic cause of infant death. SMA is recessively inherited and has a carrier frequency of 1:35 to 1:50 and an incidence of 1:6,000 to 1:10,000 live births [1,2]. The disease is caused by the homozygous loss of the survival of motor neuron 1 (SMN1) gene. Typical SMA patients show progressive degeneration of the α-motor neurons in the anterior horns of the spinal cord, eventually leading to muscle atrophy [3]. Based on the severity and age of onset, SMA is classified in five subtypes ranging from type 0, the most severe form, to type IV, the mildest form. 50% of patients suffer from severe SMA type I. Without treatment, SMA type I patients never learn to sit or walk and usually die within the first two years of life, with mean life expectancy of seven months [3]. On the other end of the spectrum, SMA type IV is a slow progressing disease, with an onset later in life (>30 years) [4]. The major underlying reason for this heterogeneity of disease expression is the unique genetic background of SMA. While homozygous loss of the disease gene SMN1 causes SMA, the gene copy number of the main modifying gene SMN2 correlates with the severity. This correlation (the more SMN2 copies, the milder the phenotype) can be explained by the genetic similarity of SMN1 and SMN2 (reviewed in [5]). During evolution, the SMN1 gene was duplicated in primates and later mutated into SMN2. Therefore, SMN1 and SMN2 differ only in 5 nucleotide exchanges, all of which do not affect the protein translation. However, the crucial difference, the translationally silent C to T transition in exon 7, disrupts an exonic splicing enhancer and creates an exonic splicing silencer, resulting in mis-splicing of SMN2 exon 7 [6,7]. In fact, only 10% of SMN2 transcripts produce a full-length protein that is functional, while 90% lack exon 7, encoding a dysfunctional protein that undergoes rapid degradation [8]. This unique genetic setting in which every patient carries at least one (usually more) copy of the major genetic modifier provides an interesting therapeutic target for SMA.