The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association

Vadla, Gangadhar P.; Singh, Kamal; Lorson, Christian L.; Lorson, Monique A.

doi:10.1016/j.bbadis.2024.167091

Cited by 2 publications

(2 citation statements)

References 39 publications

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Section: Modifiers Of Ighmbp2 Deficiencymentioning

confidence: 99%

“…It slowed the progression of motoneuron degeneration but did not restore Ighmbp2 mRNA splicing or Ighmbp2 protein in the mouse to wild-type levels [31,33]. An association between ABT1 and IGHMBP2 was shown by co-immunoprecipitation when FLAG-IGHMBP2 and myc-ABT1 were co-transfected into HEK 293T cells [31,34]. Another study by Vadal and colleagues showed that the direct, high-affinity binding of ABT1 to IGHMBP2 increased ATPase and helicase activity and the processivity of IGHMBP2 [32].…”

Section: Modifiers Of Ighmbp2 Deficiencymentioning

confidence: 99%

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Disease Mechanisms and Therapeutic Approaches in SMARD1—Insights from Animal Models and Cell Models

Jablonka,

Yildirim

2024

Biomedicines

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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a fatal childhood motoneuron disease caused by mutations in the IGHMBP2 gene. It is characterized by muscle weakness, initially affecting the distal extremities due to the degeneration of spinal α-motoneurons, and respiratory distress, due to the paralysis of the diaphragm. Infantile forms with a severe course of the disease can be distinguished from juvenile forms with a milder course. Mutations in the IGHMBP2 gene have also been found in patients with peripheral neuropathy Charcot–Marie–Tooth type 2S (CMT2S). IGHMBP2 is an ATP-dependent 5′→3′ RNA helicase thought to be involved in translational mechanisms. In recent years, several animal models representing both SMARD1 forms and CMT2S have been generated to initially study disease mechanisms. Later, the models showed very well that both stem cell therapies and the delivery of the human IGHMBP2 cDNA by AAV9 approaches (AAV9-IGHMBP2) can lead to significant improvements in disease symptoms. Therefore, the SMARD1 animal models, in addition to the cellular models, provide an inexhaustible source for obtaining knowledge of disease mechanisms, disease progression at the cellular level, and deeper insights into the development of therapies against SMARD1.

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Section: Modifiers Of Ighmbp2 Deficiencymentioning

confidence: 99%

Section: Modifiers Of Ighmbp2 Deficiencymentioning

confidence: 99%

Disease Mechanisms and Therapeutic Approaches in SMARD1—Insights from Animal Models and Cell Models

Jablonka,

Yildirim

2024

Biomedicines

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The molecular mechanisms that underlie IGHMBP2‐related diseases

Rzepnikowska,

Kaminska,

Kochański

2024

Neuropathology Appl Neurobio

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Immunoglobulin Mu‐binding protein 2 (IGHMBP2) pathogenic variants result in the fatal, neurodegenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) and the milder, Charcot–Marie‐Tooth (CMT) type 2S (CMT2S) neuropathy. More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined. The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism. Helicases are enzymes that use ATP hydrolysis to catalyse the separation of nucleic acid strands. They are involved in numerous cellular processes, including DNA repair and transcription; RNA splicing, transport, editing and degradation; ribosome biogenesis; translation; telomere maintenance; and homologous recombination. IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology. Here, we summarise our current knowledge of the clinical presentation of IGHMBP2‐related diseases. We also overview the available models, including yeast, mice and cells, which are used to study the function of IGHMBP2 and the pathogenesis of the related diseases. Further, we discuss the structure of the IGHMBP2 protein and its postulated roles in cellular functioning. Finally, we present potential anomalies that may result in the neurodegeneration observed in IGHMBP2‐related disease and highlight the most prominent ones.

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The contribution and therapeutic implications of IGHMBP2 mutations on IGHMBP2 biochemical activity and ABT1 association

Cited by 2 publications

References 39 publications

Disease Mechanisms and Therapeutic Approaches in SMARD1—Insights from Animal Models and Cell Models

Disease Mechanisms and Therapeutic Approaches in SMARD1—Insights from Animal Models and Cell Models

The molecular mechanisms that underlie IGHMBP2‐related diseases

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