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


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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  1. 1

    Fischer, U., Liu, Q. & Dreyfuss, G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell 90, 1023–1029 (1997).

    CAS  Article  Google Scholar 

  2. 2

    Lefebvre, S., Bürglen, L., Frézal, J., Munnich, A. & Melki, J. The role of the SMN gene in proximal spinal muscular atrophy. Hum. Mol. Genet. 7, 1531–1536 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Charroux, B. et al. Gemin3: a novel DEAD box protein that interacts with SMN, the spinal muscular atrophy gene product, and is a component of gems. J. Cell Biol. 147, 1181–1193 (1999).

    CAS  Article  Google Scholar 

  4. 4

    Strasswimmer, J. et al. Identification of survival motor neuron as a transcriptional activator-binding protein. Hum. Mol. Genet. 8, 1219–1226 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Campbell, L. et al. Direct interaction of Smn with dp103, a putative RNA helicase: a role for Smn in transcription regulation? Hum. Mol. Genet. 9, 1093–1100 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Meister, G. et al. Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins. Hum. Mol. Genet. 9, 1977–1986 (2000).

    CAS  Article  Google Scholar 

  7. 7

    Jablonka, S. et al. Co-regulation of survival motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy. Hum. Mol. Genet. 10, 497–505 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Pellizzoni, L., Charroux, B., Rappsilber, J., Mann, M. & Dreyfuss, G. A functional interaction between the survival motor neuron complex and RNA polymerase II. J. Cell Biol. 152, 75–85 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Mellins, R.B., Hays, A.P., Gold, A.P., Berdon, W.E. & Bowdler, J.D. Respiratory distress as the initial manifestation of Werdnig-Hoffmann disease. Pediatrics 53, 33–40 (1974).

    CAS  PubMed  Google Scholar 

  10. 10

    Bertini, E. et al. Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy. Am. J. Med. Genet. 33, 328–335 (1989).

    CAS  Article  Google Scholar 

  11. 11

    Rudnik-Schöneborn, S., Forkert, R., Hahnen, E., Wirth, B. & Zerres, K. Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropediatrics 27, 8–15 (1996).

    Article  Google Scholar 

  12. 12

    Grohmann, K. et al. Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form is linked to chromosome 11q13-q21. Am. J. Hum. Genet. 65, 1459–1462 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Zerres, K. & Davies, K.E. 59th ENMC International Workshop: Spinal Muscular Atrophies: recent progress and revised diagnostic criteria 17-19 April 1998, Soestduinen, The Netherlands. Neuromuscular Disord. 9, 272–278 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Cox, G.A., Mahaffey, C.L. & Frankel, W.N. Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele. Neuron 21, 1327–1337 (1998).

    CAS  Article  Google Scholar 

  15. 15

    Cook, S.A., Johnson, K.R., Bronson, R.T. & Davisson, M.T. Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration. Mamm. Genome 6, 187–191 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Chen, N.N., Kerr, D., Chang, C.-F., Honjo, T. & Khalili, K. Evidence for regulation of transcription and replication of the human neurotropic virus JCV genome by the human Sμbp-2 protein in glial cells. Gene 185, 55–62 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Molnar, G.M. et al. Association of the mammalian helicase MAH with the pre-mRNA splicing complex. Proc. Natl. Acad. Sci. USA 94, 7831–7836 (1997).

    CAS  Article  Google Scholar 

  18. 18

    Zhang, Q., Wang, Y.-C.J. & Montalvo, E.A. Sμbp-2 represses the Epstein-Barr virus lytic switch promoter. Virology 255, 160–170 (1999).

    Article  Google Scholar 

  19. 19

    Miao, M., Chan, S.-L., Fletcher, G.L. & Hew, C.L. The rat ortholog of the presumptive flounder antifreeze enhancer-binding protein is a helicase domain-containing protein. Eur. J. Biochem. 267, 7237–7245 (2000).

    CAS  Article  Google Scholar 

  20. 20

    McEntagart, M. et al. Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14. Am. J. Hum. Genet. 68, 1270–1276 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Wilmshurst, J.M. et al. Severe infantile axonal neuropathy with respiratory failure. Muscle Nerve 24, 760–768 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Fukita, Y. et al. The human Sμbp-2, a DNA-binding protein specific to the single-stranded guanine-rich sequence related to the immunoglobulin μ chain switch region. J. Biol. Chem. 268, 17463–17470 (1993).

    CAS  PubMed  Google Scholar 

  23. 23

    Mohan, W.S. et al. Human S mu binding protein-2 binds to the drug response element and transactivates the human apoA-I promoter: role of gemfibrozil. J. Lipid Res. 39, 255–267 (1998).

    CAS  PubMed  Google Scholar 

  24. 24

    Mizuta, T.-R., Fukita, Y., Miyoshi, T., Shimizu, A. & Honjo, T. Isolation of cDNA encoding a binding protein specific to 5′-phosphorylated single-stranded DNA with G-rich sequences. Nucleic Acids Res. 21, 1761–1766 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Grishin, N.V. The R3H motif: a domain that binds single-stranded nucleic acids. Trends Biochem. Sci. 23, 329–330 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Lorson, C.L. & Androphy, E.J. The domain encoded by exon 2 of the survival motor neuron protein mediates nucleic acid binding. Hum. Mol. Genet. 7, 1269–1275 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Grundhoff, A.T. et al. Characterization of DP103, a novel DEAD box protein that binds to the Epstein-Barr virus nuclear proteins EBNA2 and EBNA3C. J. Biol. Chem. 274, 19136–19144 (1999).

    CAS  Article  Google Scholar 

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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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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).

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