A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis

Am J Hum Genet. 2004 Nov;75(5):822-31. doi: 10.1086/425287. Epub 2004 Sep 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Calcium-Binding Proteins
  • DNA Primers
  • Kv Channel-Interacting Proteins
  • VAPB protein, human
  • Vesicular Transport Proteins
  • Green Fluorescent Proteins

Associated data

  • GENBANK/AY060395
  • GENBANK/P40075
  • GENBANK/Q16943