Human Molecular Genetics Advance Access published online on January 20, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp028
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IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1)
1 Department of Neuropediatrics, Charité University Hospital, Berlin, D-13353 Berlin, Germany 2 Department of Biology, Chemistry and Pharmacy, Free University Berlin, D-14195 Berlin, Germany 3 Theodor-Boveri-Institute, University of Würzburg, D-97074 Würzburg, Germany 4 Institute for Clinical Neurobiology, University of Würzburg, D-97074 Würzburg, Germany 5 Rudolf-Virchow-Center for Experimental Biomedicine, University of Würzburg, D-97078 Würzburg, Germany 6 University of Heidelberg, Im Neuheimer Feld 156, D-69120 Heidelberg, Germany 7 NeuroCure Clinical Research Center, Charité University Hospital, Berlin, D-10117 Berlin, Germany
Address correspondence to: Utz Fischer, Tel. +49 931 888 4029; Fax +49 931 4026; email: utz.fischer{at}biozentrum.uni-wuerzburg.de or Markus Schuelke, Tel. +49 30 4505 66468, Fax +49 30 4505 66920; email: markus.schuelke{at}charite.de
Received November 22, 2008; Revised January 13, 2009; Accepted January 13, 2009
Distal spinal muscular atrophy type 1 (DSMA1) is an autosomal recessive disease that is clinically characterized by distal limb weakness and respiratory distress. In this disease, the degeneration of 
-motoneurons is caused by mutations in the immunoglobulin µ-binding protein 2 (IGHMBP2). This protein has been implicated in DNA replication, pre-mRNA splicing and transcription, but its precise function in all these processes has remained elusive. We have purified catalytically active recombinant IGHMBP2, which has enabled us to assess its enzymatic properties and to identify its cellular targets. Our data reveal that IGHMBP2 is an ATP-dependent 5’
3’ helicase, which unwinds RNA and DNA duplices in vitro. Importantly, this helicase localizes predominantly to the cytoplasm of neuronal and non-neuronal cells and associates with ribosomes. DSMA1-causing amino acid substitutions in IGHMBP2 do not affect ribosome binding yet severely impair ATPase and helicase activity. We propose that IGHMBP2 is functionally linked to translation, and that mutations in its helicase domain interfere with this function in DSMA1 patients.
8 These authors contributed equally to this work
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