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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.
Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA)
Published in Expert Opinion on Investigational Drugs, 2022
Theodora Markati, Gemma Fisher, Sithara Ramdas, Laurent Servais
Spinal muscular atrophy (SMA) is a genetic neuromuscular disease that is characterised by progressive loss of motor neurons leading to progressive muscle weakness, atrophy, and motor and respiratory impairment. The most common form, called 5q-SMA, is caused by a homozygous deletion or loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene on locus 5q13 of chromosome 5, which codes for the homonymous survival motor neuron (SMN) protein [1,2]. 5q-SMA, henceforth called SMA, occurs in 1 in 10,000 live births and it is one of the leading genetic causes of childhood mortality. SMA is characterised by progressive initially proximal and axial muscle weakness, decreased or absent deep tendon reflexes, muscle atrophy, and – in the most severe forms without intervention – bulbar dysfunction and progressive respiratory failure as the cause of early death [3].
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].