title: A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.
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.
authors.affiliation: Human Genome Research Center, Department of Biology, Biosciences Institute, São Paulo University, São Paulo, Brazil.
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Nishimura
authors.forename: Miguel
authors.initials: M
authors.lastname: Mitne-Neto
authors.forename: Helga C A
authors.initials: HC
authors.lastname: Silva
authors.forename: Antônio
authors.initials: A
authors.lastname: Richieri-Costa
authors.forename: Susan
authors.initials: S
authors.lastname: Middleton
authors.forename: Duilio
authors.initials: D
authors.lastname: Cascio
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.forename: João R M
authors.initials: JR
authors.lastname: Oliveira
authors.forename: Tom
authors.initials: T
authors.lastname: Gillingwater
authors.forename: Jeanette
authors.initials: J
authors.lastname: Webb
authors.forename: Paul
authors.initials: P
authors.lastname: Skehel
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D001938:Brazil; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D017931:DNA Primers; D018703:Founder Effect; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D006801:Humans; D051605:Kv Channel-Interacting Proteins; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D033921:Vesicular Transport Proteins
chemical_list: D002135:Calcium-Binding Proteins; D017931:DNA Primers; D051605:Kv Channel-Interacting Proteins; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D049452:Green Fluorescent Proteins