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

Slides:



Advertisements
Similar presentations
Christina K. Marko, Balaraj B. Menon, Gang Chen, Jeffrey A
Advertisements

Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly  Julie Jerber, Maha S. Zaki, Jumana.
A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome  Stephen R.F. Twigg,
Mesial temporal lobe epilepsy associated with KCNT1 mutation
A Mutation in HOXA2 Is Responsible for Autosomal-Recessive Microtia in an Iranian Family  Fatemeh Alasti, Abdorrahim Sadeghi, Mohammad Hossein Sanati,
K. K. Noguchi, S. A. Johnson, G. A. Dissen, L. D. Martin, F. M
Figure 1 Phenotype and genotype of an undiagnosed family with autosomal recessive spastic ataxia Phenotype and genotype of an undiagnosed family with autosomal.
Mutations in FLVCR2 Are Associated with Proliferative Vasculopathy and Hydranencephaly-Hydrocephaly Syndrome (Fowler Syndrome)  Esther Meyer, Christopher.
Loss-of-Function Mutations in CAST Cause Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis, and Knuckle Pads  Zhimiao Lin, Jiahui Zhao, Daniela.
The TRIM-NHL Protein TRIM32 Activates MicroRNAs and Prevents Self-Renewal in Mouse Neural Progenitors  Jens C. Schwamborn, Eugene Berezikov, Juergen A.
Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M
Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin  Peter.
Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A
PLA2G6 Mutation Underlies Infantile Neuroaxonal Dystrophy
Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly  Julie Jerber, Maha S. Zaki, Jumana.
A Null Mutation in Inositol Polyphosphate 4-Phosphatase Type I Causes Selective Neuronal Loss in Weeble Mutant Mice  Arne Nystuen, Marie E. Legare, Leonard.
Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification 
TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy  Antonio Falace, Fabia Filipello, Veronica La Padula, Nicola.
Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease
Exome Sequencing Reveals Mutations in TRPV3 as a Cause of Olmsted Syndrome  Zhimiao Lin, Quan Chen, Mingyang Lee, Xu Cao, Jie Zhang, Donglai Ma, Long Chen,
Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest  Yao Xu, Yingli Shi, Jing Fu, Min Yu, Ruizhi Feng, Qing Sang, Bo Liang,
Polymorphisms in the Trace Amine Receptor 4 (TRAR4) Gene on Chromosome 6q23.2 Are Associated with Susceptibility to Schizophrenia  Jubao Duan, Maria Martinez,
Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females  Jennifer M. Bain, Megan T. Cho, Aida Telegrafi,
A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts 
Dan Doherty, Albert E. Chudley, Gail Coghlan, Gisele E. Ishak, A
A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution  Edgar Otto, Julia Hoefele,
Mutations in TCF4, Encoding a Class I Basic Helix-Loop-Helix Transcription Factor, Are Responsible for Pitt-Hopkins Syndrome, a Severe Epileptic Encephalopathy.
A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly  Ganeshwaran H. Mochida, Muhammad.
Minimal Purkinje Cell-Specific PCP2/L7 Promoter Virally Available for Rodents and Non- human Primates  Keisuke Nitta, Yasunori Matsuzaki, Ayumu Konno,
Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation  Marc Trimborn, Sandra M. Bell, Clive Felix, Yasmin Rashid, Hussain Jafri,
A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia  John C. van Swieten, Esther Brusse, Bianca M.
De Novo and Inherited Mutations in COL4A2, Encoding the Type IV Collagen α2 Chain Cause Porencephaly  Yuriko Yoneda, Kazuhiro Haginoya, Hiroshi Arai,
Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination  Tojo Nakayama, Almundher Al-Maawali, Malak El-Quessny,
Simon Edvardson, Claudia M. Nicolae, Pankaj B
Volume 16, Issue 6, Pages (August 2016)
The Phenotype of a Germline Mutation in PIGA: The Gene Somatically Mutated in Paroxysmal Nocturnal Hemoglobinuria  Jennifer J. Johnston, Andrea L. Gropman,
Gavin Charlesworth, Vincent Plagnol, Kira M
Volume 19, Issue 2, Pages (August 2016)
Autosomal-Dominant Woolly Hair Resulting from Disruption of Keratin 74 (KRT74), a Potential Determinant of Human Hair Texture  Yutaka Shimomura, Muhammad.
Mutations in the DBP-Deficiency Protein HSD17B4 Cause Ovarian Dysgenesis, Hearing Loss, and Ataxia of Perrault Syndrome  Sarah B. Pierce, Tom Walsh, Karen.
TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy  Antonio Falace, Fabia Filipello, Veronica La Padula, Nicola.
Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation  Asif.
Lethal Contractural Syndrome Type 3 (LCCS3) Is Caused by a Mutation in PIP5K1C, Which Encodes PIPKIγ of the Phophatidylinsitol Pathway  Ginat Narkis,
De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions  Brieana Fregeau, Bum Jun.
Physical Exercise–Induced Hypoglycemia Caused by Failed Silencing of Monocarboxylate Transporter 1 in Pancreatic β Cells  Timo Otonkoski, Hong Jiao, Nina.
Familial Hemophagocytic Lymphohistiocytosis Type 5 (FHL-5) Is Caused by Mutations in Munc18-2 and Impaired Binding to Syntaxin 11  Udo zur Stadt, Jan.
X-Linked Dominant Scapuloperoneal Myopathy Is Due to a Mutation in the Gene Encoding Four-and-a-Half-LIM Protein 1  Catarina M. Quinzii, Tuan H. Vu, K.
Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene  Silke Appenzeller, Anja Schirmacher, Hartmut Halfter,
A Usual Frameshift and Delayed Termination Codon Mutation in Keratin 5 Causes a Novel Type of Epidermolysis Bullosa Simplex with Migratory Circinate Erythema 
Stem Cell Models of Human Brain Development
Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy  Tamar.
Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M
Volume 3, Issue 3, Pages (March 2001)
A Deleterious Mutation in SAMD9 Causes Normophosphatemic Familial Tumoral Calcinosis  Orit Topaz, Margarita Indelman, Ilana Chefetz, Dan Geiger, Aryeh.
Oligodontia Is Caused by Mutation in LTBP3, the Gene Encoding Latent TGF-β Binding Protein 3  Abdul Noor, Christian Windpassinger, Irina Vitcu, Marija.
Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy  Hirotomo Saitsu,
Mutations in the Gene Encoding Capillary Morphogenesis Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis  Sandra Hanks,
Loss of Function of Glucocerebrosidase GBA2 Is Responsible for Motor Neuron Defects in Hereditary Spastic Paraplegia  Elodie Martin, Rebecca Schüle, Katrien.
Volume 22, Issue 4, Pages (January 2018)
Arun Kumar, Satish C. Girimaji, Mahesh R. Duvvari, Susan H. Blanton 
Marjorie C. Gondré-Lewis, Robert McGlynn, Steven U. Walkley 
Mutations in NEXN, a Z-Disc Gene, Are Associated with Hypertrophic Cardiomyopathy  Hu Wang, Zhaohui Li, Jizheng Wang, Kai Sun, Qiqiong Cui, Lei Song, Yubao.
Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/Threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus.
Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome  Amy E. Merrill, Barry Merriman, Claire.
A 1-month-old girl with microcephaly, global developmental delay, and seizures. A 1-month-old girl with microcephaly, global developmental delay, and seizures.
Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L
Mutations in the Fatty Acid 2-Hydroxylase Gene Are Associated with Leukodystrophy with Spastic Paraparesis and Dystonia  Simon Edvardson, Hiroko Hama,
Volume 16, Issue 4, Pages (April 2008)
A Truncating Mutation of TRAPPC9 Is Associated with Autosomal-Recessive Intellectual Disability and Postnatal Microcephaly  Ganeshwaran H. Mochida, Muhammad.
Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive 
Presentation transcript:

Microcephaly with Simplified Gyration, Epilepsy, and Infantile Diabetes Linked to Inappropriate Apoptosis of Neural Progenitors  Cathryn J. Poulton, Rachel Schot, Sima Kheradmand Kia, Marta Jones, Frans W. Verheijen, Hanka Venselaar, Marie-Claire Y. de Wit, Esther de Graaff, Aida M. Bertoli-Avella, Grazia M.S. Mancini  The American Journal of Human Genetics  Volume 89, Issue 2, Pages 265-276 (August 2011) DOI: 10.1016/j.ajhg.2011.07.006 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Pedigrees and Linkage Data (A) Simplified genealogical trees of two unrelated families with MSG, epilepsy, and PND. Filled symbols represent affected patients. A double line represents consanguinity. An asterisk represents subjects analyzed by SNP arrays and included in the linkage analysis. The results of microsatellite marker analysis confirming homozygosity are also shown. The shaded areas represent the alleles containing the mutation, and the box represents the area found by linkage analysis. (B) Output from easyLINKAGE showing an HLOD score of 4.3 for the region on chromosome 18q. The American Journal of Human Genetics 2011 89, 265-276DOI: (10.1016/j.ajhg.2011.07.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Patient Brain MRIs (A–C) MRIs from patient 1 performed at 1 year of age. (A) T1-weighted image showing a simplified gyral pattern and increased intracranial space with near-normal ventricular size. (B and C) T2-weighted coronal and axial view showing equal involvement of parietal lobes, normal cerebellum, and basal ganglia with delayed myelination. (D–F) Low-resolution MRIs from patient 2 at approximately 7 months of age. (D) Sagittal T1-weighted view showing a thin but present corpus callosum and normal brain stem. (E) T1-weighted coronal view through the hippocampus showing simplified gyration and hippocampal hypoplasia. (F) T2- weighted view, demonstrating the simplified gyral pattern and normal ventricular size. The American Journal of Human Genetics 2011 89, 265-276DOI: (10.1016/j.ajhg.2011.07.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Brain Macroscopy and Histopathology (A and B) Macroscopic view in real proportions of normal age-matched brain (upper specimen) compared with index patient 3 postmortem brain (lower specimen); note the extreme microcephaly and simplified gyration looking almost lissencephalic in its medial surface. (C and D) Macroscopic photographs of patient 3 brain, showing shallow and insufficient-in-number sulci over the whole brain surface, but more apparent in the temporal and parietal lobes. Note that photos in (C) and (D) are not in scale with those in (A) and (B). (E–J) Histopathology. (E) Histopathology of normal cerebral frontal cortex (age-matched to patient 3). (F) Patient 3 histopathology of the cerebral cortex showing numerous apoptotic neurons (arrows) and some apoptotic glial cells (H&E × 20). (G) Cerebellar folia: Purkinje neurons are apoptotic (arrows) and internal granule cell layer is diminished (H&E × 20). (H) Nearly all neurons and the inferior olivary nuclei are apoptotic. (I and J) Patient 3 pancreas stained for insulin (J), showing depletion of insulin-producing islet cells in comparison to a normal pancreas (I). The American Journal of Human Genetics 2011 89, 265-276DOI: (10.1016/j.ajhg.2011.07.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 IER3IP1 Sequence and Expression in Developing Brain (A) Schematic representation of human IER3IP1 showing the sequence, the predicted protein domains, and the location of the p.Val21Gly and p.Leu78Pro mutations. Cross-species conservation of IER3IP1 in the areas of the mutations is shown at the bottom of the diagram. Both of the predicted amino acid changes are in a highly conserved area of the gene and in the hydrophobic/transmembrane domains, and they are depicted in red. (B) Expression of Ier3ip1 at E14.5 days in the whole-mouse embryo (left); zoomed in, in the right panel is the mouse brain, with arrows pointing to increased expression in the ventricular and subventricular zone at the site of neurogenesis.24 The American Journal of Human Genetics 2011 89, 265-276DOI: (10.1016/j.ajhg.2011.07.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 5 Susceptibility of Cultured Fibroblasts to Apoptosis and TNF-α Stimulation (A) Patient cells are more susceptible to apoptosis, similar to cells from a known WRS patient, when treated with 5 mM DTT, in comparison to five control cell lines (p ≤ 0.001, unpaired t test, SPSS version 17.0). Values represent a mean of three experiments ± SEM. (B) IER3IP1 expression levels in control fibroblasts are decreased approximately 10-fold after the addition of IER3IP1 siRNA, as compared to control siRNA (p ≤ 0.001, unpaired t test, SPSS version 17.0) (left panel). Control fibroblasts treated with IER3IP1 siRNA also demonstrate a significantly increased susceptibility to apoptosis (p ≤ 0.001, unpaired t test, SPSS version 17.0) when treated with 1.25 mM DTT in comparison to control fibroblasts (right panel). Values represent a mean of three experiments ± SEM. (C) IER3 mRNA levels are increased approximately 10-fold in patient and control cells after the addition of TNF-α (left panel) (p < 0.0001, unpaired t test, SPSS version 17.0). IER3IP1 levels are increased approximately 1.5-fold in patient and control fibroblast cell lines after the addition of TNF-α (p < 0.001, unpaired t test, SPSS version 17.0) (right panel). Stars represent a significant p < 0.01 difference. The American Journal of Human Genetics 2011 89, 265-276DOI: (10.1016/j.ajhg.2011.07.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions