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.

Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase

“…A maximum logarithm of odds (LOD) score of 2.97 was identified on chromosome 12 (D12S1706 to D12S79), with most of the signal deriving from a three generational FALS kindred (MB1). No LOD scores greater than +0.8 were obtained in chromosomes [1][2][3][4][5][6][7][8][9][10][11] Author contributions: J.M., P.P., A. To whom correspondence should be addressed.…”

“…Recently, mutations have been detected in the gene encoding TAR DNA binding protein 43 (2, 3), a major component of the polyubiquitinated cytoplasmic inclusions characteristic of ALS, and the Fused in sarcoma (FUS) gene, ALS6 (4,5). Mutations have also been identified in additional genes, causing rare, atypical forms of ALS: vesicle-associated membrane protein/ synaptobrevin-associated membrane protein B gene (VAPB), which is associated both with late-onset spinal muscular atrophy and ALS, ALS8 (6); alsin, associated with juvenile onset recessive ALS, ALS2 (7); and senataxin associated with a slowly progressive form of juvenile onset ALS, ALS4 (8). Additional FALS loci have been reported for classical ALS, ALS3 on 18q identified in a single family (9), ALS with frontotemporal dementia on 9q21-q22 (10), ALS with frontotemporal dementia on chromosome 9p21.3-p13.3 (11,12), and ALS7 on chromosome 20p (13).…”

Endoplasmic reticulum architecture: structures in flux

“…Also, Nir3, a member of the highly conserved family of Nir/rdgB proteins, has a phosphatidylinositol transfer domain [37]; however, when overexpressed together with VAP-B, it causes rearrangement of the ER along circular microtubule bundles [31•], similar to the structures seen after overexpression of CLIMP-63 [28]. Interestingly, a point mutation in the VAP-B protein causes familial amyotrophic lateral sclerosis in eight Brazilian families with common Portuguese ancestry [38,39], illustrating once more the importance of cell biological studies for the understanding of disease mechanisms.…”

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

“…These genes include Sentaxin, a DNA/RNA helicase that causes juvenile ALS, 3 Alsin, 4,5 Dynactin, 6,7 angiogenin, 8 and synaptobrevin associated membrane protein B. 9 Sporadic ALS, which accounts for more than 90% of ALS cases, has been more difficult to genetically solve. In addition, a locus on chromosome 9p21, for which the gene has not yet been identified, is responsible for a form of ALS with frontotemporal lobar degeneration (FTLD).…”