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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

43 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)31-41
Number of pages11
JournalJournal of Molecular Medicine
Volume87
Issue number1
DOIs
Publication statusPublished - Jan 2009
Externally publishedYes

Keywords

  • DSMA1
  • Genotype-phenotype relation
  • IGHMBP2
  • Juvenile SMARD1
  • Mutation
  • Protein aggregation
  • Steady-state protein levels

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