A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann,

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A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann, Gudrun Nürnberg, Muhammad Farooq, Ilyas Ahmad, Thomas Alef, Hans Christian Hennies, Martin Technau, Janine Altmüller, Peter Frommolt, Holger Thiele, Angelika Anna Noegel, Peter Nürnberg The American Journal of Human Genetics Volume 90, Issue 5, Pages 871-878 (May 2012) DOI: 10.1016/j.ajhg.2012.03.016 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of an MCPH-Causing Mutation in CEP135 (A) Clinical features of two siblings of a family from northern Pakistan presenting with microcephaly, sloping forehead, and retrognathia. Informed consent to publish the photographs was obtained from the subjects' parents. (B) A simplified pedigree of the Pakistani family. Filled circles indicate individuals with MCPH. Their parents are second cousins. Only the core family is shown. DNA was available for individuals IV-1, V-1, V-2, and V-3. (C) G-banded chromosome 4 showing the position of the linkage interval at 4p14-4q12 along with the position of CEP135. The homozygous region was delimited by the markers SNP_A-2154951 (rs12498424, physical position 40,631,476 bp) and SNP_A-1894332 (rs13134527, physical position 58,702,130 bp). (D) Sequence chromatograms of a part of CEP135 exon 8 as obtained by Sanger sequencing. Traces of the male patient (V-1) and his father (IV-1) show the mutation c.970delC in homozygous and heterozygous status, respectively. The mutant sequences are shown along with a wild-type trace from a control individual. (E) Schematic representation of the genomic structure of human CEP135. The 26 exons of CEP135 are drawn to scale, while introns show just artificial lines. Black boxes represent untranslated regions. The position of mutation c.970delC in exon 8 is indicated. (F) CEP135 structure as predicted by SMART (Simple Modular Architecture Research Tool) database. This software predicted six coiled-coil domains (orange rods) which cover almost the entire region of the protein. The position of mutation p.Q324Sfs∗2 in the fourth coiled-coil domain is indicated. The American Journal of Human Genetics 2012 90, 871-878DOI: (10.1016/j.ajhg.2012.03.016) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Centrosome, Microtubule, and Nuclear Shape Defects in CEP135 Microcephalic Patient Cells (A) Immunofluorescence staining and confocal microscopy images of wild-type primary fibroblasts with well-organized microtubules and a single centrosome detected by γ-tubulin. γ-tubulin (turquoise) and α-tubulin (green) antibodies were used. DAPI (blue) was used for DNA staining. Scale bar, 5 μm. (B) Abnormality of centrosome number in CEP135 patient primary fibroblasts. Interphase cell showing supernumerary centrosomes. In this figure three centrosomes were observed as detected by γ-tubulin (turquoise). Scale bar, 5 μm. (C) Disorganized microtubule network in patient fibroblasts. Scale bar, 20 μm. (D) Control primary fibroblast showing a well-shaped ellipsoid nucleus. Scale bar, 5 μm. (E) Mutant fibroblast with a dysmorphic nucleus. Scale bar, 10 μm. (F) Graphical representation showing the number of CEP135 mutant primary fibroblasts with dysmorphic nuclei. About 20% of mutant fibroblasts harbored misshapen nuclei whereas in control fibroblasts this number was only ∼3%. Three hundred cells of each, wild-type and mutant, were counted. Error bars represent SEM, p = 3.44 × 10−03 (Student's t test). The American Journal of Human Genetics 2012 90, 871-878DOI: (10.1016/j.ajhg.2012.03.016) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Distribution of GFP-Tagged Wild-Type and Mutant CEP135 (A) N-terminally GFP-tagged human CEP135 (GFP-CEP135) was transiently expressed in COS-7 cells. GFP-CEP135 is present in dots of variable size and number. A single centrosome was detected by pericentrin-specific antibodies (turquoise). Scale bar, 5 μm. (B) COS-7 cell transfected with GFP-tagged mutant CEP135 (GFP-CEP135-mut), where diffuse staining was detected. Scale bar, 5 μm. (C) Abnormal microtubule network in COS-7 expressing wild-type CEP135. Scale bar, 5 μm. (D) COS-7 cells expressing GFP-CEP135-mut have a disorganized microtubule network. Microtubules appeared broken and concentrated near the nucleus. Scale bar, 5 μm. The American Journal of Human Genetics 2012 90, 871-878DOI: (10.1016/j.ajhg.2012.03.016) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Centrosomal and Spindle Abnormalities in COS-7 Cells Transiently Expressing Wild-Type and Mutant CEP135 (A) A GFP-CEP135-expressing cell at metaphase showing bipolar spindles with two centrosomes. (B) GFP-CEP135-mut-expressing cell with supernumerary centrosomes, which result in multipolar spindle formation. Centrosomes were detected by pericentrin-specific antibodies (turquoise). Scale bar, 5 μm. The American Journal of Human Genetics 2012 90, 871-878DOI: (10.1016/j.ajhg.2012.03.016) Copyright © 2012 The American Society of Human Genetics Terms and Conditions