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Human Molecular Genetics Advance Access published online on July 21, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh222
© 2004 by Oxford University Press
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Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Katja Grohmann 1, Wilfried Rossoll 2, Igor Kobsar 3, Bettina Holtmann 2, Sibylle Jablonka 2, Carsten Wessig 3, Gisela Stoltenburg-Didinger 4, Utz Fischer 5, Christoph Hübner 6, Rudolf Martini 3, Michael Sendtner 2*

1 Institute for Clinical Neurobiology, University of Wuerzburg, D-97080 Wuerzburg, Germany; Department of Neuropediatrics, Charité University Medical Center, D-13353 Berlin, Germany
2 Institute for Clinical Neurobiology, University of Wuerzburg, D-97080 Wuerzburg, Germany
3 Department of Neurology, University of Wuerzburg, D-97080 Wuerzburg, Germany
4 Institute for Neuropathology, Charité University Medical Center, D-13353 Berlin, Germany
5 Institute of Biochemistry, University of Wuerzburg, D-97074 Wuerzburg, Germany
6 Department of Neuropediatrics, Charité University Medical Center, D-13353 Berlin, Germany

* To whom correspondence should be addressed. E-mail: sendtner_m{at}klinik.uni-wuerzburg.de.


  Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by recessive mutations of the IGHMBP2 gene. The role of IGHMBP2 (immunoglobulin µ-binding protein 2) in the pathomechanism of motor neuron disease is unknown. We have generated antibodies against Ighmbp2 and show that low levels of Ighmbp2 immunoreactivity are present in the nucleus of spinal motor neurons and high levels in cell bodies, axons and growth cones. Ighmbp2 protein levels are strongly reduced in nmd (neuromuscular degeneration) mice, the mouse model of SMARD1. Mutant mice show severe motor neuron degeneration before first clinical symptoms become apparent. The loss of motor neuron cell bodies in lumbar spinal cord is followed by axonal degeneration in corresponding nerves such as the femoral quadriceps and sciatic nerve and loss of axon terminals at motor endplates. Motor neuron degeneration and clinical symptoms then slowly progress until the mice die at the age of 3 to 4 months. In addition, myopathic changes seem to contribute to muscle weakness and especially to the respiratory failure which is characteristic of the disorder in humans. Cultured motor neurons from embryonic nmd mice did not show any abnormality with respect to survival, axonal growth or growth cone size thus differing from motor neurons derived from, e.g., Smn deficient mice, the model of spinal muscular atrophy (SMA). Our data suggest that the pathomechanism in SMARD1 is clearly distinct from other motor neuron diseases such as classic SMA.


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