Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

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Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS Janel O. Johnson, Jessica Mandrioli, Michael Benatar, Yevgeniya Abramzon, Vivianna M. Van Deerlin, John Q. Trojanowski, J. Raphael Gibbs, Maura Brunetti, Susan Gronka, Joanne Wuu, Jinhui Ding, Leo McCluskey, Maria Martinez-Lage, Dana Falcone, Dena G. Hernandez, Sampath Arepalli, Sean Chong, Jennifer C. Schymick, Jeffrey Rothstein, Francesco Landi, Yong-Dong Wang, Andrea Calvo, Gabriele Mora, Mario Sabatelli, Maria Rosaria Monsurrò, Stefania Battistini, Fabrizio Salvi, Rossella Spataro, Patrizia Sola, Giuseppe Borghero, Giuliana Galassi, Sonja W. Scholz, J. Paul Taylor, Gabriella Restagno, Adriano Chiò, Bryan J. Traynor Neuron Volume 68, Issue 5, Pages 857-864 (December 2010) DOI: 10.1016/j.neuron.2010.11.036 Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 1 Pedigrees of Patients with VCP Mutations (A–E) Pedigrees of patients with VCP mutations. Mutant alleles are indicated by mt, whereas wild-type alleles are indicated by wt. Probands are indicated by arrows. Sex of the pedigree members is obscured to protect privacy. Pedigrees of the familial samples from the NINDS repository at Coriell have been constructed based on available family history information from the Coriell website (http://www.coriell.org/). Neuron 2010 68, 857-864DOI: (10.1016/j.neuron.2010.11.036) Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 2 Filters Applied to Variants and Indels Detected by Exome Sequencing in Affected Individuals of the ITALS#1 Pedigree Regions with LOD score greater than zero were based on linkage analysis of ITALS#1 pedigree (see also Figure S1). Variants that were found in exome data of 200 neurologically normal control subjects were filtered. Prediction of effect of variant on protein function was based on SIFT analysis (http://sift.jcvi.org/). Neuron 2010 68, 857-864DOI: (10.1016/j.neuron.2010.11.036) Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 3 Distribution of VCP Mutations Detected in Familial ALS Patients An ideogram of chromosome 9 is shown at the top. The 17 exons of VCP are numbered. Mutations detected in familial ALS cases are indicated in red, whereas mutations previously described to cause IBMPFD are shown in black. Corresponding chromatograms showing mutant and wild-type alleles are as indicated, and conservation of amino acid residue across species is highlighted at the bottom (generated using the ClustalW2 online tool, http://www.ebi.ac.uk/clustalw/). See also Figure S2 for location of mutations on VCP protein structure. Neuron 2010 68, 857-864DOI: (10.1016/j.neuron.2010.11.036) Copyright © 2010 Elsevier Inc. Terms and Conditions

Figure 4 Histopathological Images from Autopsy Tissue, Family UP731, Individual III:1 (A) Haematoxylin-eosin (H&E) stained low-power view (100×) of a lumbar spinal cord section demonstrates extensive motor neuron loss in the anterior horn, with a few remaining motor neurons (arrow). (B) Motor neurons from the hypoglossal nucleus in the medulla with abundant round eosinophilic cytoplasmic inclusions consistent with Bunina bodies (arrows), H&E, 200×. (C and D) 200× and 400×, respectively: TDP-43 immunohistochemistry on the hypoglossal nucleus shows TDP-43 positive punctate cytoplasmic inclusions with concomitant loss of nuclear stain in two motor neurons (arrows). Normal nuclear staining is preserved in the surrounding normal cells. Of note, additional tissue was not available from this autopsy. The current images were generated by removing the coverslip from selected old slides, followed by destaining and processing for TDP-43 immunohistochemistry. See also Figure S3 for histopathological images of a muscle biopsy from patient III:4 of the ITALS#1 family. Neuron 2010 68, 857-864DOI: (10.1016/j.neuron.2010.11.036) Copyright © 2010 Elsevier Inc. Terms and Conditions