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The Ighmbp2 -R604X mouse recapitulates the severe SMARD1 clinical symptoms of aspiration, respiratory and feeding
Abstract:
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (IGHMBP2). We generated the Ighmbp2 -R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial, Ighmbp2 R604X/R604X mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers. Ighmbp2 R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, Ighmbp2 R604X/R604X mice were born with visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the sciatic nerve, hindlimb neuromuscular junction and muscle pathology. Injection of the ssAAV9-WT- IGHMBP2 vector extended Ighmbp2 R604X/R604X survival a few days, due to reduced expression of the vector before death ensued. Ighmbp2 R604X/R604X phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a Ighmbp2 mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.
Insights
A new mouse model for Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) reveals critical roles for immunoglobulin mu binding protein two (IGHMBP2) in suckling and survival. This research highlights milk aspiration and impaired suckling as key factors in severe SMARD1.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Rare Diseases Research
Background:
- Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are severe genetic disorders.
- These conditions are caused by mutations in the immunoglobulin mu binding protein two (IGHMBP2) gene.
- Understanding IGHMBP2's role is crucial for developing effective therapies.
Purpose of the Study:
- To create and characterize a novel mouse model (Ighmbp2-R604X) mimicking human IGHMBP2 mutations.
- To investigate the impact of the Ighmbp2-R604X mutation on disease pathology and survival.
- To explore the specific contributions of respiratory and feeding deficits to SMARD1-like symptoms.
Main Methods:
- Generation of the Ighmbp2-R604X homozygous mutant mouse model.
- Phenotypic analysis including lifespan, weight, respiratory function, and neurological assessments.
- Histopathological examination of phrenic nerve, diaphragm, and lung tissues.
- Electrophysiological studies of hindlimb neuromuscular junctions and muscles.
- Assessment of suckling behavior and milk aspiration.
- Therapeutic intervention using ssAAV9-WT-IGHMBP2 vector.
Main Results:
- Ighmbp2(R604X/R604X) mice exhibited significantly reduced lifespan (6 days), weight loss, and failure to thrive.
- Severe respiratory distress, phrenic nerve, and diaphragm pathology were observed, consistent with SMARD1.
- Mice showed milk aspiration, lung pathology, and impaired suckling ability, evidenced by reduced milk spots.
- Hindlimb electrophysiology confirmed neuromuscular junction and muscle deficits.
- ssAAV9-WT-IGHMBP2 vector administration provided a modest survival extension.
Conclusions:
- The Ighmbp2-R604X mouse model accurately recapitulates severe SMARD1 phenotypes.
- This model demonstrates for the first time that milk aspiration and suckling deficits are critical determinants of survival in IGHMBP2-related disorders.
- Findings underscore the importance of addressing feeding and respiratory issues in SMARD1 management.
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