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Mutations in the gene encoding immunoglobulin μ-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1

Nature Genetics volume 29, pages 75–77 (2001)Cite this article

Abstract

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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Figure 1: Chest X-ray showing eventration of the right hemidiaphragm in a SMARD1 patient at 8 weeks of age.
Figure 2: Alignment of selected regions of human IGHMBP2 with orthologs of other species.
Figure 3: Segregation of IGHMBP2 mutations (restriction fragment-length polymorphism analysis).

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Acknowledgements

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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Authors and Affiliations

  1. Department of Neuropediatrics, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin, 13353, Germany

    Katja Grohmann, Markus Schuelke, Alexander Diers & Christoph Hübner

  2. Gene Mapping Center, Max Delbrueck Center for Molecular Medicine, Berlin-Buch, 13092, Germany

    Katrin Hoffmann & Barbara Lucke

  3. Division of Pediatric Neurology, Alberta Children's Hospital, University of Calgary, Calgary, T2T 5C7, Alberta, Canada

    Coleen Adams

  4. Department of Neurosciences and Unit of Molecular Medicine, Bambino Gesu' Children's Hospital, Rome, 00165, Italy

    Enrico Bertini

  5. Children's Hospital, Offenbach, Germany, 63069

    Hajnalka Leonhardt-Horti

  6. Department of Paediatrics, Hammersmith Hospital, London, W12 0HS, UK

    Francesco Muntoni

  7. Institute for Neuromuscular Research, Children's Hospital at Westmead, Parramatta, NSW 2124, Australia

    Robert Ouvrier & Jo M. Wilmshurst

  8. Institute of Human Genetics, GSF Research Institute, Neuherberg, 85764, Germany

    Arne Pfeufer

  9. Children's Hospital Neukölln, Berlin, 12051, Germany

    Rainer Rossi

  10. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Loverval, 6280, Belgium

    Lionel Van Maldergem

  11. Institute of Medical Biometry, University of Bonn, Bonn, 53105, Germany

    Thomas F. Wienker

  12. Institute of Clinical Neurobiology, University of Würzburg, Würzburg, 97080, Germany

    Michael Sendtner

  13. Department of Human Genetics, Technical University, Aachen, 52074, Germany

    Sabine Rudnik-Schöneborn & Klaus Zerres

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  1. Katja Grohmann
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Correspondence to Christoph Hübner.

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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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