De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions Niccolò E. Mencacci, Erik-Jan Kamsteeg, Kosuke Nakashima, Lea.

Slides:

Advertisements

Similar presentations

Loss of Function in Phenylketonuria Is Caused by Impaired Molecular Motions and Conformational Instability Søren W. Gersting, Kristina F. Kemter, Michael.

Advertisements

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 SLC30A10 Cause Parkinsonism and Dystonia with Hypermanganesemia, Polycythemia, and Chronic Liver Disease Marialuisa Quadri, Antonio Federico,

Mutations in AGBL1 Cause Dominant Late-Onset Fuchs Corneal Dystrophy and Alter Protein-Protein Interaction with TCF4 S. Amer Riazuddin, Shivakumar Vasanth,

Marie Sissler, Ligia Elena González-Serrano, Eric Westhof

Mutations in FLVCR2 Are Associated with Proliferative Vasculopathy and Hydranencephaly-Hydrocephaly Syndrome (Fowler Syndrome) Esther Meyer, Christopher.

Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism- Susceptibility Gene Maricela Alarcón, Brett S. Abrahams, Jennifer L.

TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy Antonio Falace, Fabia Filipello, Veronica La Padula, Nicola.

Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity Ryan J. Taft, Adeline Vanderver, Richard J. Leventer,

A De Novo Mutation in the β-Tubulin Gene TUBB4A Results in the Leukoencephalopathy Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability

Chen-Chou Wu, William J. Rice, David L. Stokes Structure

Figure 1. Generation of the S250F Aadc mutant mice

Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

Mutations of the SYCP3 Gene in Women with Recurrent Pregnancy Loss

Alternative Splicing May Not Be the Key to Proteome Complexity

Volume 24, Issue 12, Pages (December 2016)

Complex Energy Landscape of a Giant Repeat Protein

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

Efrat Avigad Laron, Emil Aamar, David Enshell-Seijffers

Mutations in a Novel Gene with Transmembrane Domains Underlie Usher Syndrome Type 3 Tarja Joensuu, Riikka Hämäläinen, Bo Yuan, Cheryl Johnson, Saara.

An RNA-Binding Multimer Specifies Nematode Sperm Fate

Peter Ianakiev, Michael W

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

Volume 15, Issue 2, Pages (February 2007)

DVL1 Frameshift Mutations Clustering in the Penultimate Exon Cause Autosomal- Dominant Robinow Syndrome Janson White, Juliana F. Mazzeu, Alexander Hoischen,

Integrative Multi-omic Analysis of Human Platelet eQTLs Reveals Alternative Start Site in Mitofusin 2 Lukas M. Simon, Edward S. Chen, Leonard C. Edelstein,

Viorica Chelban, Nisha Patel, Jana Vandrovcova, M

A Highly Strained Nuclear Conformation of the Exportin Cse1p Revealed by Molecular Dynamics Simulations Ulrich Zachariae, Helmut Grubmüller Structure

De Novo and Inherited Mutations in COL4A2, Encoding the Type IV Collagen α2 Chain Cause Porencephaly Yuriko Yoneda, Kazuhiro Haginoya, Hiroshi Arai,

Ovaries and Female Phenotype in a Girl with 46,XY Karyotype and Mutations in the CBX2 Gene Anna Biason-Lauber, Daniel Konrad, Monika Meyer, Carine deBeaufort,

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John.

RAS Proteins and Their Regulators in Human Disease

Gavin Charlesworth, Vincent Plagnol, Kira M

Gail Billingsley, Sathiyavedu T. Santhiya, Andrew D

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.

Volume 13, Issue 4, Pages (October 2015)

A De Novo Mutation in the β-Tubulin Gene TUBB4A Results in the Leukoencephalopathy Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

Mutations in HPCA Cause Autosomal-Recessive Primary Isolated Dystonia

Exome Sequencing Identifies a DYNC1H1 Mutation in a Large Pedigree with Dominant Axonal Charcot-Marie-Tooth Disease Michael N. Weedon, Robert Hastings,

Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome Fuxi Zhu, Fengsong Wang, Xiaoyu Yang, Jingjing Zhang, Huan Wu, Zhou.

Identification of Mutations in TRAPPC9, which Encodes the NIK- and IKK-β-Binding Protein, in Nonsyndromic Autosomal-Recessive Mental Retardation Asif.

DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal- Dominant Robinow Syndrome Janson J. White, Juliana F. Mazzeu, Alexander.

Meigang Gu, Kanagalaghatta R. Rajashankar, Christopher D. Lima

Volume 14, Issue 9, Pages (March 2016)

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,

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

Figure 1 Pedigree and genetic findings

A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia Niccolo E. Mencacci, Ignacio Rubio-Agusti, Anselm Zdebik, Friedrich Asmus,

Mutations in POLR3A and POLR3B Encoding RNA Polymerase III Subunits Cause an Autosomal-Recessive Hypomyelinating Leukoencephalopathy Hirotomo Saitsu,

Volume 153, Issue 7, Pages (June 2013)

Clemens C. Heikaus, Jayvardhan Pandit, Rachel E. Klevit Structure

Identification of Somatic Chromosomal Abnormalities in Hypothalamic Hamartoma Tissue at the GLI3 Locus David W. Craig, Abraham Itty, Corrie Panganiban,

Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth

Structural and Mechanistic Analysis of the Slx1-Slx4 Endonuclease

Figure 1 Schematic of the OPA3 gene and OPA3 protein isoform b

A novel homozygous FBXO43 mutation associated with male infertility and teratozoospermia in a consanguineous Chinese family Ying Ma, Ph.D., Ning Xie,

Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas Qilin Zhang, Cheng Peng,

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.

Structure of the Histone Acetyltransferase Hat1

A Novel Claudin 16 Mutation Associated with Childhood Hypercalciuria Abolishes Binding to ZO-1 and Results in Lysosomal Mistargeting Dominik Müller,

Cole-Carpenter Syndrome Is Caused by a Heterozygous Missense Mutation in P4HB Frank Rauch, Somayyeh Fahiminiya, Jacek Majewski, Jian Carrot-Zhang, Sergei.

Mutations in NOTCH1 Cause Adams-Oliver Syndrome

Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L

Mutations in HPCA Cause Autosomal-Recessive Primary Isolated Dystonia

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

Presentation transcript:

De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions Niccolò E. Mencacci, Erik-Jan Kamsteeg, Kosuke Nakashima, Lea R’Bibo, David S. Lynch, Bettina Balint, Michèl A.A.P. Willemsen, Matthew E. Adams, Sarah Wiethoff, Kazunori Suzuki, Ceri H. Davies, Joanne Ng, Esther Meyer, Liana Veneziano, Paola Giunti, Deborah Hughes, F. Lucy Raymond, Miryam Carecchio, Giovanna Zorzi, Nardo Nardocci, Chiara Barzaghi, Barbara Garavaglia, Vincenzo Salpietro, John Hardy, Alan M. Pittman, Henry Houlden, Manju A. Kurian, Haruhide Kimura, Lisenka E.L.M. Vissers, Nicholas W. Wood, Kailash P. Bhatia The American Journal of Human Genetics Volume 98, Issue 4, Pages 763-771 (April 2016) DOI: 10.1016/j.ajhg.2016.02.015 Copyright © 2016 The Authors Terms and Conditions

Figure 1 MRI Features Associated with Dominant PDE10A Mutations Axial MRI of individuals 1 (A–C) and 2 (D–F). T2-weighted imaging (A and D) and diffusion-weighted imaging (DWI; B and E) showed increased signal intensity within the striatum. In individual 1, the putamen and caudate nucleus appeared slightly swollen (A), and high signal on DWI (B) was confirmed to represent abnormal restricted diffusion on the ADC map (C). In individual 2, the abnormal signal was principally located in the postero-lateral putamina, which also appeared atrophic (D). There was no corresponding restriction of diffusion on the ADC map (F), and appearances suggested a more chronic disease stage. The American Journal of Human Genetics 2016 98, 763-771DOI: (10.1016/j.ajhg.2016.02.015) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Pedigrees, PDE10A Mutation Analysis, Interspecies Alignment, Schematic Representation of PDE10A, In Silico Modeling of the 3D Structure of the PDE10A GAF-B Domain, and Functional Studies of the Identified PDE10A Substitutions (A) Pedigrees of the three individuals carrying the de novo PDE10A mutations and Sanger sequencing confirmation of the mutations. The following abbreviations are used: WT, homozygous wild-type alleles; and M, heterozygous PDE10A mutations. (B) Interspecies alignment performed with Clustal Omega shows the complete conservation down to invertebrates of the amino acid residues affected by the substitutions. Asterisks indicate invariant residues (full conservation), whereas colons and periods represent strong and moderate similarities, respectively. (C) A schematic representation of PDE10A shows its organization in three domains: the regulatory GAF-A and GAF-B domains in the N-terminal portion of the protein and the catalytic domain in the C terminus. The p.Phe300Leu and p.Phe334Leu substitutions are both located in the GAF-B domain, which binds to cAMP. (D) In silico modeling of the 3D structure of the GAF-B domain binding pocket and its interaction with the cAMP (shown in blue) was generated with PDB: 2ZMF. The variant residues Phe300 and Phe334 and their aromatic side chains, located in the β1 and β3 sheets, respectively, forming the floor of the cAMP binding pocket, are shown in red and cyan, respectively. Both residues are located in very close proximity to the cAMP molecule and are therefore likely to play an essential role in nucleotide binding. (E) The p.Phe300Leu and p.Phe334Leu substitutions cause a loss of stimulatory effect of the GAF-B domain on PDE10A catalytic activity. The effect of cyclic nucleotides binding to the GAF-B domain on PDE activity was evaluated via measurement of the enzyme activity after WT and mutant PDE10As were incubated in the presence of various concentrations of 1-NO-cAMP and 70 nM [3H]cGMP. Each data point represents the mean ± SEM of three independent experiments. The American Journal of Human Genetics 2016 98, 763-771DOI: (10.1016/j.ajhg.2016.02.015) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Summary of PDE10A mRNA Expression in the Human and Mouse Brain (A) Boxplots of PDE10A mRNA expression levels in ten adult brain regions (source: BRAINEAC, see Web Resources). The expression levels are based on exon array experiments and are plotted on a log2 scale (y axis). This dataset was generated with Affymetrix Exon 1.0 ST arrays and brain tissue originating from 134 control individuals, collected by the Medical Research Council Sudden Death Brain and Tissue Bank and the Sun Health Research Institute, an affiliate of Sun Health Corporation.20 This plot shows significant variation in PDE10A expression across the ten brain regions analyzed, such that expression is higher in the putamen than in any other region. Abbreviations are as follows: PUTM, putamen; FCTX, frontal cortex; TCTX, temporal cortex; OCTX, occipital cortex; HIPP, hippocampus; SNIG, substantia nigra; MEDU, medulla (specifically the inferior olivary nucleus); WHMT, intralobular white matter; THAL, thalamus; CRBL, cerebellar cortex; and N, number of samples analyzed for each brain region. (B and C) PDE10A expression in the mouse brain in (B) sagittal and (C) coronal sections. PDE10A was very highly and selectively expressed in the striata and in the olfactory tubercula. Images were obtained from the Allen Mouse Brain Atlas (©2015 Allen Institute for Brain Science). Expression intensity is color coded and ranges from low (blue) to moderate (green, yellow) to high (red) intensity. The American Journal of Human Genetics 2016 98, 763-771DOI: (10.1016/j.ajhg.2016.02.015) Copyright © 2016 The Authors Terms and Conditions