Characterization of lghmbp2 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, Wilfried Rossoll, Igor Kobsar, Bettina Holtmann, Sibylle Jablonka, Carsten Wessig, Gisela Stoltenburg-Didinger, Utz Fischer, Christoph Hübner, Rudolf Martini, Michael Sendtner

Research output: Contribution to journalArticle

69 Scopus citations

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 showed 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 neuromuscular degeneration (nmd) 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 3-4 months. In addition, myopathic changes seem to contribute to muscle weakness and especially to 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 (survival motor neuron) 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.

Original languageEnglish (US)
Pages (from-to)2031-2042
Number of pages12
JournalHuman molecular genetics
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Characterization of lghmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1)'. Together they form a unique fingerprint.

  • Cite this

    Grohmann, K., Rossoll, W., Kobsar, I., Holtmann, B., Jablonka, S., Wessig, C., Stoltenburg-Didinger, G., Fischer, U., Hübner, C., Martini, R., & Sendtner, M. (2004). Characterization of lghmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1). Human molecular genetics, 13(18), 2031-2042. https://doi.org/10.1093/hmg/ddh222