Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation Marc Trimborn, Sandra M. Bell, Clive Felix, Yasmin Rashid, Hussain Jafri,

Slides:

Advertisements

Similar presentations

Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-Based Sample Rosa Rademakers, Marc Cruts,

Advertisements

Hongda Li, Stephanie L. Bielas, Maha S

Deletion of the Telomerase Reverse Transcriptase Gene and Haploinsufficiency of Telomere Maintenance in Cri du Chat Syndrome Anju Zhang, Chengyun Zheng,

Identification of a Major Susceptibility Locus for Restless Legs Syndrome on Chromosome 12q Alex Desautels, Gustavo Turecki, Jacques Montplaisir, Adolfo.

Volume 16, Issue 1, Pages (January 1996)

Localization of a Gene for Molybdenum Cofactor Deficiency, on the Short Arm of Chromosome 6, by Homozygosity Mapping Adel Shalata, Hanna Mandel, Jochen.

Mutations in the Beta Propeller WDR72 Cause Autosomal-Recessive Hypomaturation Amelogenesis Imperfecta Walid El-Sayed, David A. Parry, Roger C. Shore,

Localization of a Gene (MCUL1) for Multiple Cutaneous Leiomyomata and Uterine Fibroids to Chromosome 1q42.3-q43 N.A. Alam, S. Bevan, M. Churchman, E.

Gene Dysregulations Driven by Somatic Copy Number Aberrations-Biological and Clinical Implications in Colon Tumors Manny D. Bacolod, Francis Barany

Use of Homozygosity Mapping to Identify a Region on Chromosome 1 Bearing a Defective Gene That Causes Autosomal Recessive Homozygous Hypercholesterolemia.

Frances Busfield, David L. Duffy, Janine B. Kesting, Shelley M

Genomewide Linkage Scan Identifies a Novel Susceptibility Locus for Restless Legs Syndrome on Chromosome 9p Shenghan Chen, William G. Ondo, Shaoqi Rao,

Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

Quantitative Analysis of Survival Motor Neuron Copies: Identification of Subtle SMN1 Mutations in Patients with Spinal Muscular Atrophy, Genotype-Phenotype.

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

Jacquelyn Bond, Sheila Scott, Daniel J

Evidence for Sex-Specific Risk Alleles in Autism Spectrum Disorder

Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization Yohann Jourdy, Alexandre Janin, Mathilde Fretigny, Anne Lienhart, Claude.

I. Silveira, I. Alonso, L. Guimarães, P. Mendonça, C. Santos, P

A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts

Complement Factor H Gene Mutation Associated with Autosomal Recessive Atypical Hemolytic Uremic Syndrome Lihua Ying, Yitzhak Katz, Menachem Schlesinger,

A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

Weight Loss after Gastric Bypass Is Associated with a Variant at 15q26

Autosomal-Recessive Early-Onset Retinitis Pigmentosa Caused by a Mutation in PDE6G, the Gene Encoding the Gamma Subunit of Rod cGMP Phosphodiesterase

Highly Significant Linkage to the SLI1 Locus in an Expanded Sample of Individuals Affected by Specific Language Impairment The American Journal of.

Volume 17, Issue 7, Pages (April 2007)

Ehlers-Danlos Syndrome with Severe Early-Onset Periodontal Disease (EDS-VIII) Is a Distinct, Heterogeneous Disorder with One Predisposition Gene at Chromosome.

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

A Second Gene for Autosomal Dominant Möbius Syndrome Is Localized to Chromosome 10q, in a Dutch Family H.T.F.M. Verzijl, B. van den Helm, B. Veldman,

A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia John C. van Swieten, Esther Brusse, Bianca M.

Imprinting at the SMPD1 Locus: Implications for Acid Sphingomyelinase–Deficient Niemann-Pick Disease Calogera M. Simonaro, Jae-Ho Park, Efrat Eliyahu,

Homozygosity Haplotype Allows a Genomewide Search for the Autosomal Segments Shared among Patients Hitoshi Miyazawa, Masaaki Kato, Takuya Awata, Masakazu.

Howard B. Yeon, Noralane M. Lindor, J.G. Seidman, Christine E. Seidman

Familial Juvenile Hyperuricemic Nephropathy: Localization of the Gene on Chromosome 16p11.2—and Evidence for Genetic Heterogeneity Blanka Stibůrková,

Assessment of the Effect of Age at Onset on Linkage to Bipolar Disorder: Evidence on Chromosomes 18p and 21q Ping-I Lin, Melvin G. McInnis, James B.

Localization of a Gene for Benign Adult Familial Myoclonic Epilepsy to Chromosome 8q23.3-q24.1 Masaaki Mikami, Takeshi Yasuda, Akira Terao, Masayuki.

Disruption of Contactin 4 (CNTN4) Results in Developmental Delay and Other Features of 3p Deletion Syndrome Thomas Fernandez, Thomas Morgan, Nicole Davis,

High-Resolution Molecular Characterization of 15q11-q13 Rearrangements by Array Comparative Genomic Hybridization (Array CGH) with Detection of Gene Dosage

Molecular and Fluorescence In Situ Hybridization Characterization of the Breakpoints in 46 Large Supernumerary Marker 15 Chromosomes Reveals an Unexpected.

Localization of a Gene for Duane Retraction Syndrome to Chromosome 2q31 Binoy Appukuttan, Elizabeth Gillanders, Suh-Hang Juo, Diana Freas-Lutz, Sandra.

Koji Suzuki, Tania Bustos, Richard A. Spritz

Linkage Analysis Identifies a Novel Locus for Restless Legs Syndrome on Chromosome 2q in a South Tyrolean Population Isolate Irene Pichler, Fabio Marroni,

Gene Dysregulations Driven by Somatic Copy Number Aberrations-Biological and Clinical Implications in Colon Tumors Manny D. Bacolod, Francis Barany

Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization Yohann Jourdy, Alexandre Janin, Mathilde Fretigny, Anne Lienhart, Claude.

Long Homozygous Chromosomal Segments in Reference Families from the Centre d'Étude du Polymorphisme Humain Karl W. Broman, James L. Weber The American.

Maspardin Is Mutated in Mast Syndrome, a Complicated Form of Hereditary Spastic Paraplegia Associated with Dementia Michael A. Simpson, Harold Cross,

Localization of the Fourth Locus (GLC1E) For Adult-Onset Primary Open-Angle Glaucoma to the 10p15-p14 Region Mansoor Sarfarazi, Anne Child, Diliana Stoilova,

Increased DNA Methylation at the AXIN1 Gene in a Monozygotic Twin from a Pair Discordant for a Caudal Duplication Anomaly N.A. Oates, J. van Vliet, D.L.

Douglas F. Levinson, Matthew D. Levinson, Ricardo Segurado, Cathryn M

A Progressive Autosomal Recessive Cataract Locus Maps to Chromosome 9q13-q22 Elise Héon, Andrew D. Paterson, Michael Fraser, Gail Billingsley, Megan Priston,

Genomewide Search and Genetic Localization of a Second Gene Associated with Autosomal Dominant Branchio-Oto-Renal Syndrome: Clinical and Genetic Implications

Hongda Li, Stephanie L. Bielas, Maha S

Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety of Cancers Nicolas Sévenet, Eammon Sheridan, Daniel Amram, Pascale Schneider,

Marjolijn C. J. Jongmans, Eugene T. P

Arun Kumar, Satish C. Girimaji, Mahesh R. Duvvari, Susan H. Blanton

Identification, by Homozygosity Mapping, of a Novel Locus for Autosomal Recessive Congenital Ichthyosis on Chromosome 17p, and Evidence for Further Genetic.

The DNA-Based Structure of Human Chromosome 5 in Interphase

Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy Laura S. Kremer, Felix Distelmaier,

A Gene for an Autosomal Dominant Scleroatrophic Syndrome Predisposing to Skin Cancer (Huriez Syndrome) Maps to Chromosome 4q23 Young-Ae Lee, Howard P.

Identification and Characterization of a Mutation, in the Human UDP-Galactose-4- Epimerase Gene, Associated with Generalized Epimerase-Deficiency Galactosemia

Heritability of Cellular Radiosensitivity: A Marker of Low-Penetrance Predisposition Genes in Breast Cancer? S.A. Roberts, A.R. Spreadborough, B. Bulman,

Variable CD7 Expression on T Cells in the Leukemic Phase of Cutaneous T Cell Lymphoma (Sézary Syndrome) Eric C. Vonderheid, Amy Kotecha, Christine M.

Assignment of the Muscle-Eye-Brain Disease Gene to 1p32-p34 by Linkage Analysis and Homozygosity Mapping Bru Cormand, Kristiina Avela, Helena Pihko,

Microcephaly with Simplified Gyration, Epilepsy, and Infantile Diabetes Linked to Inappropriate Apoptosis of Neural Progenitors Cathryn J. Poulton, Rachel.

Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/Threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus.

Quantitative Analysis of Survival Motor Neuron Copies: Identification of Subtle SMN1 Mutations in Patients with Spinal Muscular Atrophy, Genotype-Phenotype.

Exon Skipping in IVD RNA Processing in Isovaleric Acidemia Caused by Point Mutations in the Coding Region of the IVD Gene Jerry Vockley, Peter K. Rogan,

A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly Ganeshwaran H. Mochida, Muhammad.

Mark Gibbs, Janet L. Stanford, Gail P

Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-Based Sample Rosa Rademakers, Marc Cruts,

Presentation transcript:

Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation Marc Trimborn, Sandra M. Bell, Clive Felix, Yasmin Rashid, Hussain Jafri, Paul D. Griffiths, Luitgard M. Neumann, Alice Krebs, André Reis, Karl Sperling, Heidemarie Neitzel, Andrew P. Jackson The American Journal of Human Genetics Volume 75, Issue 2, Pages 261-266 (August 2004) DOI: 10.1086/422855 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Depiction of the 64-cM homozygous region, identified by a genomewide search, in consanguineous siblings with PCC syndrome. The region of homozygous markers is boxed. Maximum two-point LOD scores of 1.37 (θ=0) were obtained for markers D8S264, D8S277, D8S550, and D8S560. The American Journal of Human Genetics 2004 75, 261-266DOI: (10.1086/422855) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Findings indicating that MCPH1 primary microcephaly and PCC syndrome are allelic disorders. Patients with MCPH1 primary microcephaly (black diamonds) and patients with PCC syndrome (unblackened squares) have a similar degree of microcephaly, and both groups also exhibit short stature of varying severity. a, Head circumference (OFC), height, and weight, plotted as SDs relative to the appropriate age- and sex-related population mean. b and c, Neuroimaging in MCPH1 primary microcephaly, demonstrating a small but structurally normal brain. In PCC syndrome, however, there is more marked gyral simplification resembling pachygyria (d), and periventricular neuronal heterotopias are also present (e). Subjects include an adult with MCPH1 primary microcephaly (b, T1W sagittal; c, axial T2W) and an 18-mo–old child with PCC syndrome (d, axial T2W; e, axial T1W and T2W images of lateral ventricles). f–h, MRI scans of normal subjects age matched to those of images b–d, respectively. The scale bar is 1 cm. The American Journal of Human Genetics 2004 75, 261-266DOI: (10.1086/422855) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Premature chromosome condensation, present in both MCPH1 primary microcephaly and PCC syndrome. Shown are prophase-like cells in peripheral blood lymphocytes of patients with MCPH1 primary microcephaly (a) and patients with PCC syndrome (b). The American Journal of Human Genetics 2004 75, 261-266DOI: (10.1086/422855) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 Homozygous ins427A mutation (arrow) of the MCPH1 gene, which is present in patients with PCC syndrome. The American Journal of Human Genetics 2004 75, 261-266DOI: (10.1086/422855) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 5 The siRNA-mediated depletion of MCPH1 is sufficient to cause premature chromosome condensation. a, Prophase-like phenotype observed in HeLa cells after siRNA-mediated depletion of MCPH1. A marked increase in prophase cells is seen after MCPH1 siRNA transfection in HeLa and LN9SV fibroblasts (b), whereas there is no significant change in mitotic index (% metaphases) (c). The American Journal of Human Genetics 2004 75, 261-266DOI: (10.1086/422855) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 6 Delayed decondensation observed in MCPH1-deficient cells. a, Binucleate MCPH1 mutant cell with condensed chromosomes indicating a delay in decondensation. b, Binucleate control lymphoblastoid cell with decondensed chromatin. c, Proportion of cells with condensed chromosomes postmitosis in patient and control cell lines. Many cytochalasin-treated binucleate G1-phase PCC (29%) and MCPH1 (36%) mutant cells show condensed chromatin, compared with control lymphoblastoid cells (4%). The American Journal of Human Genetics 2004 75, 261-266DOI: (10.1086/422855) Copyright © 2004 The American Society of Human Genetics Terms and Conditions