Muchow, R. | bioRxiv Science

bioRxiv2025

The Ighmbp2-R604X mouse recapitulates the severe SMARD1 clinical symptoms of aspiration, respiratory and feeding deficits

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, Ighmbp2R604X/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. Ighmbp2R604X/R604X mice also presented with signs of milk aspiration and lung pathology. Interestingly, Ighmbp2R604X/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 Ighmbp2R604X/R604X survival a few days, due to reduced expression of the vector before death ensued. Ighmbp2R604X/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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/672633v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e783b0org.highwire.dtl.DTLVardef@176cea5org.highwire.dtl.DTLVardef@f8b570org.highwire.dtl.DTLVardef@4fea4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2025

The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E

Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2,500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. Several Nefl mouse models exist that either alter the mouse Nefl gene or overexpress a mutated human NEFL transgene, each recapitulating various aspects of CMT2E disease. We generated the orthologous NEFLE396K mutation in the mouse C57BL/6 background, NeflE397K. In a separate report, we extensively characterized the electrophysiology deficits and axon pathology in NeflE397K mice. In this manuscript, we report our characterization of NeflE397K motor function deficits, muscle pathology and changes in breathing Nefl+/E397K and NeflE397K/E397K mice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally, Nefl+/E397K and NeflE397K/E397K mice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly, Nefl mutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions. NeflE397K/E397K mice phenotypes and pathology were consistently more severe than Nefl+/E397K mice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.

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