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Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy  Kornelia Neveling,

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Presentation on theme: "Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy  Kornelia Neveling,"— Presentation transcript:

1 Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy  Kornelia Neveling, Lilian A. Martinez-Carrera, Irmgard Hölker, Angelien Heister, Aad Verrips, Seyyed Mohsen Hosseini-Barkooie, Christian Gilissen, Sascha Vermeer, Maartje Pennings, Rowdy Meijer, Margot te Riele, Catharina J.M. Frijns, Oksana Suchowersky, Linda MacLaren, Sabine Rudnik-Schöneborn, Richard J. Sinke, Klaus Zerres, R. Brian Lowry, Henny H. Lemmink, Lutz Garbes, Joris A. Veltman, Helenius J. Schelhaas, Hans Scheffer, Brunhilde Wirth  The American Journal of Human Genetics  Volume 92, Issue 6, Pages (June 2013) DOI: /j.ajhg Copyright © 2013 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Identified BICD2 Mutations and Their Chromosomal Positions
(A, E, and G) Pedigrees of families 1 (A), 2 (E), and 3 (G). (B) An ideogram of chromosome 9 shows the linked region and the flanking SNPs identified in family 1. (C) An ideogram of BICD2 includes exon and intron structure and the identified variants. (D, F, and H) A sequence of the region includes the mutation and the corresponding region of the unaffected parent in families 1 (D), 2 (F), and 3 (H). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Schematic Drawing of BICD2 and Its Interaction Partners
The diagram depicts a simplified structure of human BICD2. Indicated are the five coiled-coil domains, which are typically combined as coiled-coil domains 1–3. Numbers indicate the respective amino acid residues. In the upper part of the diagram, known interaction partners of the respective coiled-coil domains are given. Please note that the interaction with FMRP is RNA mediated and the interaction between clathrin heavy chain (CLHC) and BICD2 has only been shown for Drosophila so far. In the lower part of the diagram, the four identified variants and a multispecies alignment of the affected amino acids are given. Protein sequences were aligned with blastp. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Effect of the Mutant BICD2 Alleles on the Golgi Apparatus
(A–P) HeLa cells were transfected with tGFP-BICD2 pCMV6-AC cDNA (either wild-type [A–C] or with BICD2 missense variants [D–P]). Cells were fixed and stained for a specific Golgi marker, Giantin (red) (1:100, Abcam), and DAPI (blue) (Life Technologies). Only transfected cells glowed green under the fluorescent microscope and allowed an easy comparison with untransfected cells, which reflected the wild-type situation. For better visibility, the Giantin staining alone is shown in the middle row and the inset in the right row, which represents an enlarged Golgi of a transfected cell. Scale bars represent 20 μm. (A–C) The cells transfected with the wild-type construct show a condensed and abundant Golgi structure. (D–P) Compared to wild-type or nontransfected cells, cells transfected with the three mutant cDNA constructs and the rare variant show a fragmented Golgi with a very diffuse and faint signal. (Q) Quantification of cells with fragmented Golgi; 70–100 cells were counted for each experiment (n = 3) and are shown as the mean ± SD. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Mutations in BICD2 Cause Severe Golgi Fragmentation in Primary Fibroblasts (A) Immunoblot analyses of primary-fibroblast proteins of one control cell line and two cell lines derived from affected individuals. The cells were stained with BICD2 and β-actin as a loading control. (B) Quantification of the immunoblot shows reduced BICD2 levels in fibroblast lines isolated from affected individuals. (C) Golgi structures, defined as condensed, intermedium, or diffuse in 100 cells of each cell line, were counted in three independent experiments and are given as the mean ± SD. Each quantification was done blindly by two independent persons. Statistical significance is given between controls and each of the two cell lines as ∗∗∗p < 0.001, ∗∗p < 0.01, or ∗p < The following abbreviation is used: ns, not significant. (D–O) Immunostaining of control (D, G, J, and M) and disease (E, F, H, I, K, L, N, and O) fibroblasts with antibodies against trans-Golgi marker p230 in green (1:100, BD Transduction Laboratories) and BICD2 in red (1:200, Sigma), as well as merged pictures, are shown. The nucleus is stained with DAPI in blue. (M), (N), and (O) show magnified insets of single cells from (J), (K), and (L), respectively. Note that compared to control fibroblasts, affected fibroblasts show strongly fragmented Golgi and BICD2 trapped in the Golgi. Scale bars represent 20 μm. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

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