A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis Agnes L. Nishimura, Miguel.

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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 The American Journal of Human Genetics Volume 75, Issue 5, Pages 822-831 (November 2004) DOI: 10.1086/425287 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Mapping of the VAPB locus and mutation analyses. a, Pedigree from the first family reported with a diagnosis of ALS/MND (an asterisk [*] indicates DNA was available). b, VAPB locus at 20q13.3. Recombinant events reduced the region to 1.5 Mb, between marker D20S430 and the TUBB1 gene. The American Journal of Human Genetics 2004 75, 822-831DOI: (10.1086/425287) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Analyses of VAPB gene. a, Chromatogram showing the mutation in VAPB coding sequence and normal control. b, Segregation of the P56S mutation in heterozygous patients and normal controls (homozygous). The HaeIII enzyme cuts in several fragments, producing one major allele of 179 bp in normal subjects and one allele of 207 bp in heterozygous patients. c, Partial amino alignment of the VAP homologues genes. Gaps were introduced for optimal alignment. Lengths of each partial protein are indicated. The amino acid sequence FKVKTTAPRXYCVRPNS is highly conserved (blue), and the proline is indicated (red). d, Haplotype analysis of three kindred studied. All the patients have a common haplotype (red), which was not present in normal relatives (green). e, VAPB models. The top part of the β sandwich is made of green β strands, and the bottom part is made of red strands. Wild type induces a kink and splits half of the strand into the top part of the sandwich (green) and the other half of the strand into the bottom part (red). The P56S mutation disrupts the hydrogen bonds between strands on the same sheet of the β sandwich, favoring new hydrogen bonds that move the bottom half to the opposite side of the β sandwich. The American Journal of Human Genetics 2004 75, 822-831DOI: (10.1086/425287) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 GFP expression in hippocampal neurons and HEK293 cell culture. a, Neurons and HEK cells expressing the VAPB wild type (green). b, Using an ER marker (red), we observed a colocalization of the VAPB and ER compartment (yellow), as reported elsewhere (only the colocalization is shown). c, P56S mutant disrupts the subcellular distribution, showing intracellular aggregates. d–e, P56S mutant does not colocalize either with Golgi apparatus (blue) or with the ER (red). The American Journal of Human Genetics 2004 75, 822-831DOI: (10.1086/425287) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure A1 Supplemental Figure Pedigrees from families studied. a, Family 2: white family with diagnosis of atypical ALS. b, Family 3: African Brazilian family with diagnosis of atypical ALS. c, Family 4: white family with diagnosis of typical ALS and atypical ALS. d, Family 5: African Brazilian family with diagnosis of mild SMA. e, Family 6: white family with diagnosis of late-onset SMA type Finkel. f, Family 7: African Brazilian family with diagnosis of late-onset SMA type Finkel. It was not possible to link all these subjects to the same pedigree; however, all patients tested have the same P56S mutation in the VAPB gene. An asterisk (*) indicates DNA was available. The American Journal of Human Genetics 2004 75, 822-831DOI: (10.1086/425287) Copyright © 2004 The American Society of Human Genetics Terms and Conditions