The <i>Ighmbp2</i>D564N mouse model is the first SMARD1 model to demonstrate respiratory defects

Smith, Caley E.; Lorson, Monique A.; Hernandez, Sara M Ricardez; Rawi, Zayd Al; Mao, Jiude; Marquez, José; Villalón, Eric; Keilholz, Amy N; Smith, Catherine L.; Garro-Kacher, Mona O; Morcos, Toni I.; Davis, Daniel R.; Bryda, Elizabeth C.; Nichols, Nicole L.; Lorson, Christian L.

doi:10.1093/hmg/ddab317

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…Furthermore, as mentioned above, the intra-familiar variability of phenotypes suggests the presence of factors that may modify the clinical course of the disease. The mouse genetic factors on chromosome 13 influenced the onset and progression of the disease in a SMARD1 mouse model described in [ 21 , 59 , 60 ]. Note that similarly protective allele also in humans cannot be excluded, and this additionally complicates the overall picture of the disease.…”

Section: Discussionmentioning

confidence: 99%

Validation of the Pathogenic Effect of IGHMBP2 Gene Mutations Based on Yeast S. cerevisiae Model

Rzepnikowska

Kamińska

Kochański

2022

IJMS

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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a heritable neurodegenerative disease characterized by rapid respiratory failure within the first months of life and progressive muscle weakness and wasting. Although the causative gene, IGHMBP2, is well defined, information on IGHMBP2 mutations is not always sufficient to diagnose particular patients, as the gene is highly polymorphic and the pathogenicity of many gene variants is unknown. In this study, we generated a simple yeast model to establish the significance of IGHMBP2 variants for disease development, especially those that are missense mutations. We have shown that cDNA of the human gene encodes protein which is functional in yeast cells and different pathogenic mutations affect this functionality. Furthermore, there is a correlation between the phenotype estimated in in vitro studies and our results, indicating that our model may be used to quickly and simply distinguish between pathogenic and non-pathogenic mutations identified in IGHMBP2 in patients.

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Section: Discussionmentioning

confidence: 99%

Validation of the Pathogenic Effect of IGHMBP2 Gene Mutations Based on Yeast S. cerevisiae Model

Rzepnikowska

Kamińska

Kochański

2022

IJMS

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“…AAV9 has tropism for many CNS tissues as well as peripheral tissues. AAV9 has the ability to enter neuronal and non-neural cells (astrocytes and microglia) in the CNS (30,(49)(50)(51)(52). Viral particles were generated in HEK293T cells (ATCC® CRL-3216 TM ) and purified using three CsCl density-gradient ultracentrifugation steps followed by dialysis against PBS buffer as previously described (48,53).…”

Section: Generation Of Scaav9-abt1 Virus and Icv Injectionsmentioning

confidence: 99%

“…Motor function was evaluated using the time-to-right assay from P7-26. Each pup was placed on its back and the time it takes for the pup to turn over and stabilize on all four paws was recorded (50,54). The maximum attempted time was 30 seconds.…”

Section: Motor Function Testsmentioning

confidence: 99%

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ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity

Vadla¹,

Hernandez²,

Mao³

et al. 2023

JCI Insight

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1. Ownership: CLL is co-founder and chief scientific officer of Shift Pharmaceuticals. 2. Income: CLL has received in excess of $10,000 in income per annum from Shift Pharmaceuticals. 3. Research support. Research in the CLL and MAL labs have been supported by subawards from Shift Pharmaceuticals (as part of grants from the DOD, CMT Research Foundation and the NIH). 4. Intellectual property. CLL and MU share patents on novel compounds licensed by Shift Pharmaceuticals and planned patents for additional novel compounds. MAL and ZCL are associated with Shift by family relation. SAH was formerly employed by Shift Pharmaceuticals. KS is chief scientific officer for Sanctum Therapeutics Corporation. 1. Ownership: KS is chief scientific officer of Sanctum Therapeutics Corporation. 2. Income: KS has received in excess of $10,000 in income per annum from Sanctum Therapeutics Corporation. 3. Intellectual property. KS and MU share patents on novel compounds licensed by Sanctum Therapeutics Corporation and planned patents for additional novel compounds.

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“…Interestingly, FTD exists on a disease spectrum with ALS and mutations in TBK1 have been identified as causative of both ALS and FTD ( Cirulli et al, 2015 ; Freischmidt et al, 2015 ; Pottier et al, 2015 ) highlighting the potential role of DHX58 in these diseases. Furthermore, mutations in the RNA helicase IGHMBP2 which result in a loss of function are attributed to spinal muscular atrophy with respiratory distress type I (SMARD1) ( Guenther et al, 2007 ; Smith et al, 2021 ) and Charcot-Marie tooth disease type 2 ( Cottenie et al, 2014 ).…”

Section: Rna Helicases Associated With Microsatellite Repeat Expansio...mentioning

confidence: 99%

RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration

et al. 2022

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Short repeated sequences of 3−6 nucleotides are causing a growing number of over 50 microsatellite expansion disorders, which mainly present with neurodegenerative features. Although considered rare diseases in relation to the relatively low number of cases, these primarily adult-onset conditions, often debilitating and fatal in absence of a cure, collectively pose a large burden on healthcare systems in an ageing world population. The pathological mechanisms driving disease onset are complex implicating several non-exclusive mechanisms of neuronal injury linked to RNA and protein toxic gain- and loss- of functions. Adding to the complexity of pathogenesis, microsatellite repeat expansions are polymorphic and found in coding as well as in non-coding regions of genes. They form secondary and tertiary structures involving G-quadruplexes and atypical helices in repeated GC-rich sequences. Unwinding of these structures by RNA helicases plays multiple roles in the expression of genes including repeat-associated non-AUG (RAN) translation of polymeric-repeat proteins with aggregating and cytotoxic properties. Here, we will briefly review the pathogenic mechanisms mediated by microsatellite repeat expansions prior to focus on the RNA helicases eIF4A, DDX3X and DHX36 which act as modifiers of RAN translation in C9ORF72-linked amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72-ALS/FTD) and Fragile X-associated tremor/ataxia syndrome (FXTAS). We will further review the RNA helicases DDX5/17, DHX9, Dicer and UPF1 which play additional roles in the dysregulation of RNA metabolism in repeat expansion disorders. In addition, we will contrast these with the roles of other RNA helicases such as DDX19/20, senataxin and others which have been associated with neurodegeneration independently of microsatellite repeat expansions. Finally, we will discuss the challenges and potential opportunities that are associated with the targeting of RNA helicases for the development of future therapeutic approaches.

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The Ighmbp2D564N mouse model is the first SMARD1 model to demonstrate respiratory defects

Cited by 10 publications

References 40 publications

Validation of the Pathogenic Effect of IGHMBP2 Gene Mutations Based on Yeast S. cerevisiae Model

Validation of the Pathogenic Effect of IGHMBP2 Gene Mutations Based on Yeast S. cerevisiae Model

ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity

RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration

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