Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal- Dominant Dowling-Degos Disease F. Buket Basmanav, Ana-Maria Oprisoreanu,

Slides:

Advertisements

Similar presentations

Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal- Dominant Dowling-Degos Disease F. Buket Basmanav, Ana-Maria Oprisoreanu,

Advertisements

A Mutation in the 5′-UTR of IFITM5 Creates an In-Frame Start Codon and Causes Autosomal-Dominant Osteogenesis Imperfecta Type V with Hyperplastic Callus

Loss-of-Function Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with Central- Complex and Radial-Spoke Defects Esther Kott, Marie Legendre, Bruno.

Volume 85, Issue 1, Pages (January 2014)

CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria Carol Saunders,

The Small-Molecule Iron Transport Inhibitor Ferristatin/NSC Promotes Degradation of the Transferrin Receptor Lior Horonchik, Marianne Wessling-Resnick

Pericentrosomal Localization of the TIG3 Tumor Suppressor Requires an N-Terminal Hydrophilic Region Motif Tiffany M. Scharadin, Gautam Adhikary, Kristin.

Volume 133, Issue 4, Pages (October 2007)

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

Volume 48, Issue 4, Pages (November 2012)

The vacuolar-ATPase B1 subunit in distal tubular acidosis: novel mutations and mechanisms for dysfunction D.G. Fuster, J. Zhang, X.-S. Xie, O.W. Moe

A Nonsense Mutation in the Human Homolog of Drosophila rogdi Causes Kohlschutter– Tonz Syndrome Adi Mory, Efrat Dagan, Barbara Illi, Philippe Duquesnoy,

Pathogenicity of POFUT1 in Dowling-Degos Disease: Additional Mutations and Clinical Overlap with Reticulate Acropigmentation of Kitamura F. Buket Basmanav,

S100A7 (Psoriasin) – Mechanism of Antibacterial Action in Wounds

Volume 126, Issue 7, Pages (June 2004)

A Missense Mutation in PRPF6 Causes Impairment of pre-mRNA Splicing and Autosomal-Dominant Retinitis Pigmentosa Goranka Tanackovic, Adriana Ransijn,

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

Volume 9, Issue 2, Pages (February 2002)

Missense Mutations in SLC26A8, Encoding a Sperm-Specific Activator of CFTR, Are Associated with Human Asthenozoospermia Thassadite Dirami, Baptiste Rode,

Mutations in AQP5, Encoding a Water-Channel Protein, Cause Autosomal-Dominant Diffuse Nonepidermolytic Palmoplantar Keratoderma Diana C. Blaydon, Lisbet K.

Mutational Spectrum of d-Bifunctional Protein Deficiency and Structure-Based Genotype-Phenotype Analysis Sacha Ferdinandusse, Mari S. Ylianttila, Jolein.

Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic.

Molecular Characterization of Loss-of-Function Mutations in PCSK9 and Identification of a Compound Heterozygote Zhenze Zhao, Yetsa Tuakli-Wosornu, Thomas.

Exome Sequencing and Functional Analysis Identifies BANF1 Mutation as the Cause of a Hereditary Progeroid Syndrome Xose S. Puente, Victor Quesada, Fernando G.

CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria Carol Saunders,

Somatic Mutations in NEK9 Cause Nevus Comedonicus

Karin U. Schallreuter Journal of Investigative Dermatology

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms Karin Weiss,

Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis Akiharu Kubo, Aiko.

Hailey–Hailey Disease: Identification of Novel Mutations in ATP2C1 and Effect of Missense Mutation A528P on Protein Expression Levels Rebecca J. Fairclough,

The Spinal Muscular Atrophy Disease Gene Product, SMN, and Its Associated Protein SIP1 Are in a Complex with Spliceosomal snRNP Proteins Qing Liu, Utz.

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility Tailai Chen, Yuehong Bian, Xiaoman Liu, Shigang Zhao, Keliang.

Coiled Coils Direct Assembly of a Cold-Activated TRP Channel

Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex Sandra M. Pasternack, Melanie Refke,

Volume 24, Issue 10, Pages (October 2016)

Yanhui Xu, Yu Chen, Ping Zhang, Philip D. Jeffrey, Yigong Shi

Volume 6, Issue 6, Pages (December 2000)

Mutations in the AIRE Gene: Effects on Subcellular Location and Transactivation Function of the Autoimmune Polyendocrinopathy-Candidiasis–Ectodermal Dystrophy.

RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes Ludovic Jeanson, Bruno Copin, Jean-François.

Glycine Substitution Mutations Cause Intracellular Accumulation of Collagen XVII and Affect Its Post-Translational Modifications Laura Huilaja, Tiina.

A Heterozygous Truncating Mutation in RRM2B Causes Autosomal-Dominant Progressive External Ophthalmoplegia with Multiple mtDNA Deletions Henna Tyynismaa,

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.

Structural Basis of EZH2 Recognition by EED

Jorge A. Garces, Imran B. Clark, David I. Meyer, Richard B. Vallee

A Novel Dominant Mutation in Plakoglobin Causes Arrhythmogenic Right Ventricular Cardiomyopathy Angeliki Asimaki, Petros Syrris, Thomas Wichter, Paul.

Mutations in FEZF1 Cause Kallmann Syndrome

J. Fielding Hejtmancik, Xiaodong Jiao, Anren Li, Yuri V

Analyses of the Effects That Disease-Causing Missense Mutations Have on the Structure and Function of the Winged-Helix Protein FOXC1 Ramsey A. Saleem,

Volume 8, Issue 4, Pages (October 2010)

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.

Structure of the BRCT Repeats of BRCA1 Bound to a BACH1 Phosphopeptide

Involvement of PIAS1 in the Sumoylation of Tumor Suppressor p53

Mutations in the AIRE Gene: Effects on Subcellular Location and Transactivation Function of the Autoimmune Polyendocrinopathy-Candidiasis–Ectodermal Dystrophy.

IgG Autoantibodies from Bullous Pemphigoid (BP) Patients Bind Antigenic Sites on Both the Extracellular and the Intracellular Domains of the BP Antigen.

Expression of FcRn, the MHC Class I-Related Receptor for IgG, in Human Keratinocytes Karla Cauza, Gabriele Hinterhuber, Ruth Dingelmaier-Hovorka, Karin.

Volume 16, Issue 3, Pages (March 2008)

ST3GAL3 Mutations Impair the Development of Higher Cognitive Functions

Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects Lia Boyle, Mirjam M.C. Wamelink,

Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic.

Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein GPSM2 as the Cause of Nonsyndromic Hearing Loss DFNB82

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.

Gain-of-Function Mutation of KIT Ligand on Melanin Synthesis Causes Familial Progressive Hyperpigmentation Zhi-Qiang Wang, Lizhen Si, Quan Tang, Debao.

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

Gene Augmentation and Readthrough Rescue Channelopathy in an iPSC-RPE Model of Congenital Blindness Pawan K. Shahi, Dalton Hermans, Divya Sinha, Simran.

Volume 97, Issue 5, Pages (September 2009)

Mutation Analysis of CHRNA1, CHRNB1, CHRND, and RAPSN Genes in Multiple Pterygium Syndrome/Fetal Akinesia Patients Julie Vogt, Benjamin J. Harrison,

Three Families with Autosomal Dominant Nephrogenic Diabetes Insipidus Caused by Aquaporin-2 Mutations in the C-Terminus Michio Kuwahara, Kazuyuki Iwai,

Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex Maria-Teresa Romano, Aylar Tafazzoli, Maximilian.

Mutational Spectrum of d-Bifunctional Protein Deficiency and Structure-Based Genotype-Phenotype Analysis Sacha Ferdinandusse, Mari S. Ylianttila, Jolein.

Presentation transcript:

Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal- Dominant Dowling-Degos Disease F. Buket Basmanav, Ana-Maria Oprisoreanu, Sandra M. Pasternack, Holger Thiele, Günter Fritz, Jörg Wenzel, Leopold Größer, Maria Wehner, Sabrina Wolf, Christina Fagerberg, Anette Bygum, Janine Altmüller, Arno Rütten, Laurent Parmentier, Laila El Shabrawi- Caelen, Christian Hafner, Peter Nürnberg, Roland Kruse, Susanne Schoch, Sandra Hanneken, Regina C. Betz The American Journal of Human Genetics Volume 94, Issue 1, Pages 135-143 (January 2014) DOI: 10.1016/j.ajhg.2013.12.003 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Appearance and Pedigrees (A–F) Reticulate hyperpigmentation and hyperkeratotic brown papules on the back (A), breast (B), trunk (C), arm (D), and legs (E and F) of affected individuals. (G and H) Pedigrees with two affected individuals. Affected family members are shown in black; circles and squares denote females and males, respectively. Both individuals II:1 (G and H) were used for exome sequencing. The American Journal of Human Genetics 2014 94, 135-143DOI: (10.1016/j.ajhg.2013.12.003) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Position of Mutations in POGLUT1 and Verification of Mutations Identified by Exome Sequencing (A) Cartoon depicting the exon structure of POGLUT1. All identified mutations are marked by arrow heads. The mutations are defined on nucleotide and protein levels. The number of individuals carrying each mutation is denoted with the number of squares. Red squares indicate mutations identified by exome sequencing. (B) All three mutations identified by exome sequencing were verified by Sanger sequencing. The mutated sequences are given in comparison to WT sequences. The American Journal of Human Genetics 2014 94, 135-143DOI: (10.1016/j.ajhg.2013.12.003) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Protein Modeling of Wild-Type and Mutant POGLUT1 (A) POGLUT1 is composed of two major domains; the N-terminal domain (residues 1–180; green) and the C-terminal domain (residues 181–349; magenta) together form a binding pocket for the substrate UDP-glucose (stick model; yellow) at the domain interface. A long C-terminal helix (residues 350–384; blue) stabilizes the arrangement of the two domains. (B) Arg279 is critically involved in UDP-glucose binding forming two salt bridges to oxygen atoms of the diphosphate moiety of UDP-glucose. UDP-glucose is shown as stick model with carbon shown in yellow, nitrogen in blue, phosphor in orange, and oxygen in red. Arg279 is shown as stick model with carbon in magenta and nitrogen atoms in blue. The salt bridges are indicated as broken lines. (C) Sequence analysis showing the mutant and WT sequences for the missense mutation leading to substitution of an arginine residue with tryptophan (c.835C>T [p.Arg279Trp]). (D) Partial amino acid sequence of human POGLUT1 in comparison with orthologs from other species. Arginine residue depicted with red is highly conserved across different species. (E) p.Arg279Trp leads to the substitution of this arginine residue with tryptophan. Loss of the interaction between arginine and the phosphate group of UDP-glucose will largely decrease the affinity to the substrate. Moreover, the large side chain of Trp279 in the mutant form of the enzyme might block the access of UDP-glucose. The side chain of Trp279 is shown as stick model and Van-der-Waals spheres in cyan. The American Journal of Human Genetics 2014 94, 135-143DOI: (10.1016/j.ajhg.2013.12.003) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 Immunohistochemistry on Skin Biopsies, Immunoblotting, and Immunofluorescence Analysis of HEK293T cells Transiently Expressing Wild-Type and Mutant POGLUT1 (A) For immunohistochemistry, sections were prepared from formalin-fixed, paraffin-embedded skin biopsies obtained by plastic surgery from individuals with DDD and healthy controls. POGLUT1 localization was analyzed with the polyclonal antibody NBP1-90311 (named KTELC1; Novus Biologicals) at a 1:500 dilution. Visualization was performed with the LSAB2 staining kit (DAKO) with Fast Red Chromogen. POGLUT1 was strongly present in the epidermis of healthy controls, especially in the upper parts (the stratum spinosum and stratum granulosum). POGLUT1 staining was weaker in lesional skin of individuals affected by DDD. (B) For immunoblotting, WT sequence, sequence bearing mutation c.652C>T (p.Arg218∗), and sequence bearing mutation c.835C>T (p.Arg279Trp) were cloned into the eukaryotic expression vector pAAV-CMV-MCS (Stratagene). HEK293T cells (European Collection of Cell Cultures [ECACC]) were transiently transfected with the plasmids by the use of Lipofectamine 2000 (Invitrogen) according to the manufacturer’s instructions. Forty-eight hr after transfection, cells were lysed in ice cold lysis buffer (50 mM HEPES pH 7.5, 150 mM NaCl, 1% Triton X-100) supplemented with proteinase inhibitors (Roche) for 30 min on ice followed by sonication and centrifugation at 14.000 rpm/10 min/4°C. Clear supernatant was boiled with SDS-sample buffer at 95°C for 5 min and the proteins were subjected to gel electrophoresis (SDS-PAGE, 10%) followed by transfer to nitrocellulose membrane (Millipore). Immunoblotting was performed with mouse anti-Flag (1804; Sigma Aldrich, 1:1.000), rabbit anti-POGLUT1 (NBP1-90311; Novus Biologicals, 1:1.000) primary antibodies and IRDye secondary antibodies (IRDye 800 goat anti-mouse and IRDye 680 goat anti-rabbit, 1:10.000). Bands of the expected size were detected for the WT POGLUT1 and the protein with the p.Arg279Trp substitution, whereas the nonsense mutation (c.652C>T [p.Arg218∗]) led to translation of a truncated protein of around 30 kDa. (C) Immunofluorescence analysis was performed with transiently transfected HEK293T cells. Cells were fixed and incubated for 12–14 hr with mouse anti-Flag (1:400, Sigma-Aldrich) and rabbit anti-PDI (1:200, Abcam) antibodies. After several washing steps, cells were incubated for 40 min with Alexa Fluor 488 goat anti-rabbit, Alexa Fluor 568 goat anti-mouse (1:300, Invitrogen), and DAPI (Invitrogen). Images were acquired at room temperature with a laser-scanning confocal microscope (Nikon A1/Ti, Nikon) with a CFI Plan Apochromat infrared 60× water-immersion objective (NA 1.27). For each construct z stack (step: 0.250 um), images were taken with the NIS-Elements 4.0 acquisition software (Nikon). The analysis revealed the colocalization of the WT POGLUT1 with endoplasmic reticulum (ER). No significant difference was observed in localization patterns of the WT protein and the protein with the amino acid substitution. However, a more aggregated pattern was observed for the truncated protein in comparison to the WT protein, which coincided with an impaired colocalization with the ER. Abbreviations are as follows: HC, healthy control; DDD, Dowling-Degos disease, IB, immunoblot. The American Journal of Human Genetics 2014 94, 135-143DOI: (10.1016/j.ajhg.2013.12.003) Copyright © 2014 The American Society of Human Genetics Terms and Conditions