A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.
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.
Nishimura
Agnes L
AL
Human Genome Research Center, Department of Biology, Biosciences Institute, São Paulo University, São Paulo, Brazil.
Mitne-Neto
Miguel
M
Silva
Helga C A
HC
Richieri-Costa
Antônio
A
Middleton
Susan
S
Cascio
Duilio
D
Kok
Fernando
F
Oliveira
João R M
JR
Gillingwater
Tom
T
Webb
Jeanette
J
Skehel
Paul
P
Zatz
Mayana
M
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
D002135:Calcium-Binding Proteins; D017931:DNA Primers; D051605:Kv Channel-Interacting Proteins; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D049452:Green Fluorescent Proteins