A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis

Agnes L Nishimura, Miguel Mitne-Neto, Helga C A Silva, Antônio Richieri-Costa, Susan Middleton, Duilio Cascio, Fernando Kok, João R M Oliveira, Tom Gillingwater, Jeanette Webb, Paul Skehel, Mayana Zatz

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.

Original languageEnglish
Pages (from-to)822-31
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - Nov 2004

Keywords / Materials (for Non-textual outputs)

  • Adult
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis
  • Brazil
  • Calcium-Binding Proteins
  • Cells, Cultured
  • Chromosome Mapping
  • Chromosomes, Human, Pair 20
  • DNA Primers
  • Founder Effect
  • Gene Expression
  • Green Fluorescent Proteins
  • Humans
  • Kv Channel-Interacting Proteins
  • Middle Aged
  • Models, Molecular
  • Molecular Sequence Data
  • Muscular Atrophy, Spinal
  • Mutation, Missense
  • Pedigree
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Vesicular Transport Proteins


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