Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription1,2,3,4,5,6,7,8. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA9,10,11,12,13. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin μ-binding protein 2 (IGHMBP2; on chromosome 11q13.2–q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse15, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus16,17,18,19. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.
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We thank the patients and their families for participation in the study. The help, discussions and critical comments on this manuscript of C. Bassir, M. Bollinger, S. Buttenberg, E. Eike, A. Huebner, A.Y. Manzur, J. Scholz, G. Stoltenburg-Didinger and A. Zwirner are acknowledged. This study has been supported by grants from the Deutsche Forschungsgemeinschaft (Hu 408/3-1, K.G. and C.H.; Ze 205/10-1, S.R.-S. and K.Z.; SFB 581, TPB1, M.S., Würzburg) and in part by the parents' support group 'Helft dem muskelkranken Kind', Hamburg, Germany (C.H.).
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Grohmann, K., Schuelke, M., Diers, A. et al. Mutations in the gene encoding immunoglobulin μ-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 29, 75–77 (2001). https://doi.org/10.1038/ng703
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