Human Molecular Genetics Advance Access originally published online on March 19, 2009
Human Molecular Genetics 2009 18(12):2115-2126; doi:10.1093/hmg/ddp134
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Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery
1 Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6100, USA 2 Department of Cell Biology and Ecology, Faculty of Biology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain 3 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
* To whom correspondence should be addressed. Tel: +1 2157460014; Email: mourelaz{at}uphs.upenn.edu
Received March 4, 2009; Accepted March 17, 2009
The human motor neuron degenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by loss of function mutations of immunoglobulin µ-binding protein 2 (IGHMBP2), a protein of unknown function that contains DNA/RNA helicase and nucleic acid-binding domains. Reduced IGHMBP2 protein levels in neuromuscular degeneration (nmd) mice, the mouse model of SMARD1, lead to motor neuron degeneration. We report the biochemical characterization of IGHMBP2 and the isolation of a modifier locus that rescues the phenotype and motor neuron degeneration of nmd mice. We find that a 166 kb BAC transgene derived from CAST/EiJ mice and containing tRNA genes and activator of basal transcription 1 (Abt1), a protein-coding gene that is required for ribosome biogenesis, contains the genetic modifier responsible for motor neuron rescue. Our biochemical investigations show that IGHMBP2 associates physically with tRNAs and in particular with tRNATyr, which are present in the modifier and with the ABT1 protein. We find that transcription factor IIIC-220 kDa (TFIIIC220), an essential factor required for tRNA transcription, and the helicases Reptin and Pontin, which function in transcription and in ribosome biogenesis, are also part of IGHMBP2-containing complexes. Our findings strongly suggest that IGHMBP2 is a component of the translational machinery and that these components can be manipulated genetically to suppress motor neuron degeneration.