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

  • Ulf-Peter Guenther
  • Lusy Handoko
  • Raymonda Varon
  • Ulrich Stephani
  • Chang-Yong Tsao
  • Jerry R. Mendell
  • Susanne Lützkendorf
  • Christoph Hübner
  • Katja von Au
  • Sibylle Jablonka
  • Gunnar Dittmar
  • Udo Heinemann
  • Anja Schuetz
  • Markus Schuelke
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.gif (70 kb)
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).

109_2008_402_Fig1_ESM.tif (4.6 mb)
High resolution image file (TIF 4.8 MB)
109_2008_402_Fig2_ESM.gif (142 kb)
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).

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

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Ulf-Peter Guenther
    • 1
    • 2
  • Lusy Handoko
    • 4
  • Raymonda Varon
    • 5
  • Ulrich Stephani
    • 6
  • Chang-Yong Tsao
    • 7
  • Jerry R. Mendell
    • 7
  • Susanne Lützkendorf
    • 1
  • Christoph Hübner
    • 1
  • Katja von Au
    • 1
  • Sibylle Jablonka
    • 8
  • Gunnar Dittmar
    • 9
  • Udo Heinemann
    • 10
  • Anja Schuetz
    • 10
  • Markus Schuelke
    • 1
    • 3
  1. 1.Department of NeuropediatricsCharité University Medical School of BerlinBerlinGermany
  2. 2.Department of Biology, Chemistry and PharmacyFree University BerlinBerlinGermany
  3. 3.NeuroCure Clinical Research CenterCharité University Medical SchoolBerlinGermany
  4. 4.Institute of BiochemistryUniversity of WuerzburgWuerzburgGermany
  5. 5.Institute of Human GeneticsCharité University Medical SchoolBerlinGermany
  6. 6.Department of NeuropediatricsUniversity Hospital KielKielGermany
  7. 7.Nationwide Children’s HospitalOhio State UniversityColumbusUSA
  8. 8.Institute for Clinical NeurobiologyUniversity of WuerzburgWuerzburgGermany
  9. 9.Mass Spectrometry Core UnitMax-Delbrück Center for Molecular MedicineBerlinGermany
  10. 10.Protein Sample Production FacilityMax-Delbrück Center for Molecular MedicineBerlinGermany