title: 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.
abstract: Distal spinal muscular atrophy type 1 (DSMA1) is caused by mutations in the immunoglobulin mu-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.
authors.affiliation: Department of Neuropediatrics, Charité University Medical School of Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Ulf-Peter
authors.initials: UP
authors.lastname: Guenther
authors.forename: Lusy
authors.initials: L
authors.lastname: Handoko
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.forename: Chang-Yong
authors.initials: CY
authors.lastname: Tsao
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Susanne
authors.initials: S
authors.lastname: Lützkendorf
authors.forename: Christoph
authors.initials: C
authors.lastname: Hübner
authors.forename: Katja
authors.initials: K
authors.lastname: von Au
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jablonka
authors.forename: Gunnar
authors.initials: G
authors.lastname: Dittmar
authors.forename: Udo
authors.initials: U
authors.lastname: Heinemann
authors.forename: Anja
authors.initials: A
authors.lastname: Schuetz
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
mesh_terms: D000328:Adult; D017668:Age of Onset; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D011247:Pregnancy; D047928:Premature Birth; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C489892:IGHMBP2 protein, human; D014157:Transcription Factors