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Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease

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Abstract

Distal spinal muscular atrophy type 1 (DSMA1) is caused by mutations in the immunoglobulin μ-binding protein 2 (IGHMBP2) gene. Patients with DSMA1 present between 6 weeks and 6 months of age with progressive muscle weakness and respiratory failure due to diaphragmatic palsy. Contrary to this “classic” infantile disease, we have previously described a DSMA1 patient with juvenile disease onset. In this paper, we present (1) a second juvenile case and (2) the first study of DSMA1 on protein level in patients with infantile (n = 3) as well as juvenile (n = 2) disease onset observing elevated residual steady-state IGHMBP2 protein levels in the patients with late onset DSMA1 as compared to those with classic DSMA1. Mutation screening in IGHMBP2 revealed two patients compound heterozygous for a novel missense mutation (c.1478C→T; p.T493I) and another previously described mutation. In lymphoblastoid cells of both patients, steady-state IGHMBP2 protein levels were reduced. In comparison to wild-type IGHMBP2, the p.T493I variant protein had an increased tendency to aggregate and spontaneously degrade in vitro. We verified a change in the physicochemical properties of the p.T493I variant which may explain the pathogenicity of this mutation. Our data further suggest that the age of onset of DSMA1 is variable, and we discuss the effect of residual IGHMBP2 protein levels on the clinical course and the severity of the disease.

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Acknowledgments

We thank the patients and their families for participation in this study. G. Koch, Children’s Hospital Hagen, and A. Hahn, Department of Neuropediatrics, Kiel University, contributed to the medical management of one patient. We thank Véronique Dutrannoy for providing HPRT primers and help in the RT-PCR TaqMan assay and Dr. Dietrich Carlhoff from GE Healthcare for his continuous help and counseling regarding the ÄKTA FPLC system. The work was supported by grants of the Deutsche Forschungsgemeinschaft (HU 408/3-2 and HU 408/3-3), the Charité (Rahel-Hirsch-Fellowship to K.v.A.), and by a generous donation of the parents’ self help group “Helft dem muskelkranken Kind, Hamburg e.V.”. The Protein Sample Production Facility at the Max Delbrück Center is funded by the Helmholtz Association of German Research Centers.

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Authors and Affiliations

  1. Department of Neuropediatrics, Charité University Medical School of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Ulf-Peter Guenther, Susanne Lützkendorf, Christoph Hübner, Katja von Au & Markus Schuelke

  2. Department of Biology, Chemistry and Pharmacy, Free University Berlin, Berlin, Germany

    Ulf-Peter Guenther

  3. NeuroCure Clinical Research Center, Charité University Medical School, Berlin, Germany

    Markus Schuelke

  4. Institute of Biochemistry, University of Wuerzburg, Wuerzburg, Germany

    Lusy Handoko

  5. Institute of Human Genetics, Charité University Medical School, Berlin, Germany

    Raymonda Varon

  6. Department of Neuropediatrics, University Hospital Kiel, Kiel, Germany

    Ulrich Stephani

  7. Nationwide Children’s Hospital, Ohio State University, Columbus, OH, USA

    Chang-Yong Tsao & Jerry R. Mendell

  8. Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany

    Sibylle Jablonka

  9. Mass Spectrometry Core Unit, Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Gunnar Dittmar

  10. Protein Sample Production Facility, Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Udo Heinemann & Anja Schuetz

Authors
  1. Ulf-Peter Guenther
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  2. Lusy Handoko
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  3. Raymonda Varon
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  4. Ulrich Stephani
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  5. Chang-Yong Tsao
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  9. Katja von Au
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  10. Sibylle Jablonka
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  12. Udo Heinemann
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  13. Anja Schuetz
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  14. Markus Schuelke
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Corresponding authors

Correspondence to Anja Schuetz or Markus Schuelke.

Electronic supplementary material

Below is the image is a link to a high resolution version.

ESM Fig. 1

Pedigrees of the two families with segregation of the various mutations. All mutations are numbered according to the IGHMBP2 protein sequence NP_002171 and the nomenclature suggested by den Dunnen et al. [17] (GIF 71 KB).

High resolution image file (TIF 4.8 MB)

ESM Fig. 2

Multiple alignment of IGHMBP2 orthologs shows the high evolutionary conservation of the amino acid p.T493. The p.T493I mutation is located within the helicase domain, but outside of the canonical helicase motifs. Homologous sequences were retrieved from Genbank (http://www.ncbi.nlm.nih.gov/) and the Ensembl database (http://www.ensembl.org) with the following accession numbers: NP_012908.1; NP_565299; P40694; ENSPTRP00000006865; ENSMMUP00000013244; ENSBTAT0000002993; ENSCAFP00000015816; ENSGALP00000006890; ENSCINP00000010526; ENSDARP00000060290; ENSXETP00000043180 (GIF 141 KB).

High resolution image file (TIF 6.6 MB)

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Guenther, UP., Handoko, L., Varon, R. et al. Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease. J Mol Med 87, 31–41 (2009). https://doi.org/10.1007/s00109-008-0402-7

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  • DOI: https://doi.org/10.1007/s00109-008-0402-7

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