title: Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery.
abstract: The human motor neuron degenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by loss of function mutations of immunoglobulin mu-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 tRNA(Tyr), 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6100, USA.
authors.forename: Mariàngels
authors.initials: M
authors.lastname: de Planell-Saguer
authors.forename: David G
authors.initials: DG
authors.lastname: Schroeder
authors.forename: Maria Celina
authors.initials: MC
authors.lastname: Rodicio
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Zissimos
authors.initials: Z
authors.lastname: Mourelatos
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D012365:RNA, Transfer, Tyr / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D035165:Transcription Factors, General / Q000235:genetics / Q000378:metabolism
chemical_list: C485754:Abt1 protein, mouse; D004268:DNA-Binding Proteins; C081225:Ighmbp2 protein, mouse; D009687:Nuclear Proteins; D012365:RNA, Transfer, Tyr; D014157:Transcription Factors; D035165:Transcription Factors, General