Mutations in Centrosomal Protein CEP152 in Primary Microcephaly Families Linked to MCPH4 Duane L. Guernsey, Haiyan Jiang, Julie Hussin, Marc Arnold,

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Mutations in Centrosomal Protein CEP152 in Primary Microcephaly Families Linked to MCPH4 Duane L. Guernsey, Haiyan Jiang, Julie Hussin, Marc Arnold, Khalil Bouyakdan, Scott Perry, Tina Babineau-Sturk, Jill Beis, Nadine Dumas, Susan C. Evans, Meghan Ferguson, Makoto Matsuoka, Christine Macgillivray, Mathew Nightingale, Lysanne Patry, Andrea L. Rideout, Aidan Thomas, Andrew Orr, Ingrid Hoffmann, Jacques L. Michaud, Philip Awadalla, David C. Meek, Mark Ludman, Mark E. Samuels The American Journal of Human Genetics Volume 87, Issue 1, Pages 40-51 (July 2010) DOI: 10.1016/j.ajhg.2010.06.003 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Maritime Microcephaly Cohort (A–C) Maritime families 1–3 of patients carrying mutations in the CEP152 gene. Affected probands are represented by fully shaded symbols, noted by arrowheads. (D) Photograph of microcephalic patient 1937 (with mother). (E and F) MRI scans of the head of patient 1937 at the age of 18 yrs. The American Journal of Human Genetics 2010 87, 40-51DOI: (10.1016/j.ajhg.2010.06.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Growth Charts Tracking the Head Circumference of Our Microcephalic Patients from an Early Age Compared to Population Means for Girls and Boys Solid lines show the mean head size at various ages. Dashed lines show the limits of two standard deviations above or below the mean size. (A) Females: x represents patient 1669, dotted circle represents patient 1937. (B) Males: x represents patient 1672. The American Journal of Human Genetics 2010 87, 40-51DOI: (10.1016/j.ajhg.2010.06.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Sequences of Affected Patients Carrying Mutations in CEP152 The upper part of each panel shows wild-type amino acid sequence above, mutant amino acid sequence below. The lower part of each panel shows four chromatogram traces; uppermost and lowermost are virtual forward and reverse traces, respectively, created by the software from the consensus wild-type sequence, and inner traces are forward and reverse chromatograms, respectively, from the patient sample. The two center tracks are mutation-detection calls by MutationSurveyor for forward and reverse sequences; peaks above the green curve reach significance according to the software calling algorithm. The red arrows points to the mutations in the affected patient's forward and reverse sequences. (A) Homozygous mutation p.Q265P in CEP152 in patient 1669 with PM. (B) Heterozygous mutation p.R987X in CEP152 in patient 1937 with PM. The American Journal of Human Genetics 2010 87, 40-51DOI: (10.1016/j.ajhg.2010.06.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Sequence Analysis of CEP152 (A) Multiple sequence alignment of CEP152 in human and other vertebrates in the region surrounding mutated residue Q265. The mutation to proline is indicated by a P above the human sequence. (B) Domain structures of CEP152 predicted by NCBI. Red arrows indicate the approximate location of mutations at residues 265 (Q-to-P in coiled-coil domain SMC_prok_B) and 987 (truncating domain SMC_prok_A). (C) Coiled-coil domain predictions for wild-type and p.Q265P mutant CEP152 for four bioinformatic tools. The American Journal of Human Genetics 2010 87, 40-51DOI: (10.1016/j.ajhg.2010.06.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 5 Expression of CEP152 in Embryonic Mouse Brains RT-PCR was performed on stage 12.5 or 14.5 embryonic brain RNA with the use of primers designed to amplify across multiple splice junctions of the mouse orthologous gene. The American Journal of Human Genetics 2010 87, 40-51DOI: (10.1016/j.ajhg.2010.06.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 6 Functional Analysis of CEP152 Mutants Human cells were transfected with vectors expressing either wild-type or mutant human CEP152 fused to GFP. In each row, the left panel shows antibody staining to γ-tubulin to mark centrosomes; the center panel shows GFP fluorescence; the right panel shows merged γ-tubulin plus GFP plus Hoechst, with insert at a higher magnification of centrosomes. Top row: cells transfected with vector alone (just GFP); middle row, cells transfected with wild-type CEP152-GFP fusion; bottom row, cells transfected with p.R987X mutant CEP152-GFP fusion. Scale bar represents 5 μm. The American Journal of Human Genetics 2010 87, 40-51DOI: (10.1016/j.ajhg.2010.06.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 7 Selection Analysis of CEP152 in Vertebrates (A) Phylogenetic tree and ω ratios for CEP152 coding sequences. For all branches, the ω ratio is set free to vary. The maximum-likelihood estimate of ω is shown along each branch. (B) Log likelihood values and parameter estimates under different branch models. The parameters in each model are the 16 branch lengths of the tree (number of nucleotide substitutions per codon), the transition/ transversion rate ratio κ, and the ω ratio(s). Estimates of branch lengths and κ are not shown. To test whether the human ratio is significantly different from the others, we focused specifically on comparisons among the human (H), primates (P), and other (O) lineages. ωH, ωP, and ω0 are thus the dN/dS ratios for branches H, P, and all other branches, respectively. Significant model comparison: B (H0) and D (H1): p = 1.23 × 10−2, fixed-ratio models (H0) and free-ratio (H1): p < 10−10. (C) Sites of CEP152 under potential positive selection in humans. The log likelihood ratio test supports the branch-site model of positive selection with p = 2.62 × 10−2 for the general test. P(ω > 1) are the posterior probabilities of specific potential sites under positive selection in the human lineage. The American Journal of Human Genetics 2010 87, 40-51DOI: (10.1016/j.ajhg.2010.06.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions