Abstract
Immunoglobulin mu binding protein 2 (IGHMBP2) is a DNA/RNA helicase with a putative role in transcriptional regulation and splicing. A recessive mutation of the Ighmbp2 gene in neuromuscular degeneration (nmd) mice causes progressive neurogenic atrophy of limb muscles. Affected mice show significant loss of motor neurons with large caliber axons and a moderate reduction of neurons with small caliber axons in the ventral nerve roots of the spinal cord. To investigate the role of Ighmbp2 in the pathogenesis of neuromuscular degeneration, we generated two independent lines of transgenic mice expressing the full-length Ighmbp2 cDNA specifically in neurons. Histopathological evaluation of L4 ventral nerve roots revealed that transgenic expression of the Ighmbp2 cDNA prevented primary motor neuron degeneration, while restoring the normal axonal morphology and density in nmd mice. A similar neuronal improvement is found in mutant mice carrying the CAST/EiJ-derived modifier of nmd (Mnm(C)). Intriguingly, both the transgenic and modified nmd mice went on to develop a previously unobserved cardiac and skeletal myopathy. Necropsy of nmd mice in end-stage heart failure revealed a primary dilated cardiomyopathy with secondary respiratory failure that was confirmed by in vivo ECG and echocardiographic measures. Our results suggest that reduced levels of IGHMBP2 in nmd mice compromise the integrity and function not only of motor neurons but also of skeletal and cardiac myocytes. These findings highlight the important role of IGHMBP2 in the maintenance and survival of these terminally differentiated cell types.