Journal of Molecular Medicine

, Volume 87, Issue 1, pp 31–41

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

Authors

  • Ulf-Peter Guenther
    • Department of NeuropediatricsCharité University Medical School of Berlin
    • Department of Biology, Chemistry and PharmacyFree University Berlin
  • Lusy Handoko
    • Institute of BiochemistryUniversity of Wuerzburg
  • Raymonda Varon
    • Institute of Human GeneticsCharité University Medical School
  • Ulrich Stephani
    • Department of NeuropediatricsUniversity Hospital Kiel
  • Chang-Yong Tsao
    • Nationwide Children’s HospitalOhio State University
  • Jerry R. Mendell
    • Nationwide Children’s HospitalOhio State University
  • Susanne Lützkendorf
    • Department of NeuropediatricsCharité University Medical School of Berlin
  • Christoph Hübner
    • Department of NeuropediatricsCharité University Medical School of Berlin
  • Katja von Au
    • Department of NeuropediatricsCharité University Medical School of Berlin
  • Sibylle Jablonka
    • Institute for Clinical NeurobiologyUniversity of Wuerzburg
  • Gunnar Dittmar
    • Mass Spectrometry Core UnitMax-Delbrück Center for Molecular Medicine
  • Udo Heinemann
    • Protein Sample Production FacilityMax-Delbrück Center for Molecular Medicine
    • Protein Sample Production FacilityMax-Delbrück Center for Molecular Medicine
    • Department of NeuropediatricsCharité University Medical School of Berlin
    • NeuroCure Clinical Research CenterCharité University Medical School
Original Article

DOI: 10.1007/s00109-008-0402-7

Cite this article as:
Guenther, U., Handoko, L., Varon, R. et al. J Mol Med (2009) 87: 31. doi:10.1007/s00109-008-0402-7

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.

Keywords

IGHMBP2DSMA1Juvenile SMARD1MutationSteady-state protein levelsProtein aggregationGenotype–phenotype relation

Supplementary material

109_2008_402_Fig1_ESM.tif (4.6 mb)
High resolution image file (TIF 4.8 MB)
109_2008_402_Fig2_ESM.tif (6.3 mb)
High resolution image file (TIF 6.6 MB)

Copyright information

© Springer-Verlag 2008