Missense Mutations in GJB2 Encoding Connexin-26 Cause the Ectodermal Dysplasia Keratitis-Ichthyosis-Deafness Syndrome Gabriele Richard, Fatima Rouan,

Slides:

Advertisements

Similar presentations

Date of download: 6/2/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Is the Loose Anagen Hair Syndrome a Keratin Disorder?

Advertisements

A Novel Missense Mutation in the Second Extracellular Domain of GJB2, p.Ser183Phe, Causes a Syndrome of Focal Palmoplantar Keratoderma with Deafness

Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

Genetic Heterogeneity of Pseudoxanthoma Elasticum: The Chinese Signature Profile of ABCC6 and ENPP1 Mutations Liang Jin, Qiujie Jiang, Zhengsheng Wu,

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

A Novel Mutation and Large Size Polymorphism Affecting the V2 Domain of Keratin 1 in an African-American Family with Severe, Diffuse Palmoplantar Keratoderma.

Epidermolysis Bullosa Simplex Caused by Distal Truncation of BPAG1-e: An Intermediate Generalized Phenotype with Prurigo Papules Iana Turcan, Anna M.G.

Expression of Transglutaminase 5 in Normal and Pathologic Human Epidermis Eleonora Candi, Sergio Oddi, Andrea Paradisi, Alessandro Terrinoni, Marco Ranalli,

Genetic Diseases of Junctions

P. M. Kelley, D. J. Harris, B. C. Comer, J. W. Askew, T. Fowler, S. D

Gene-Targeted Next Generation Sequencing Identifies PNPLA1 Mutations in Patients with a Phenotypic Spectrum of Autosomal Recessive Congenital Ichthyosis:

Transient Bullous Dermolysis of the Newborn Associated with Compound Heterozygosity for Recessive and Dominant COL7A1 Mutations Nadja Hammami-Hauasli,

Transglutaminase 5 Expression in Human Hair Follicle

Jennifer A. Easton, Steven Donnelly, Miriam A. F. Kamps, Peter M

Basement Membrane Zone Remodeling During Appendageal Development in Human Fetal Skin. The Absence of Type VII Collagen is Associated with Gelatinase-A.

Connexins 26, 30, and 43: Differences Among Spontaneous, Chronic, and Accelerated Human Wound Healing Johanna M. Brandner, Pia Houdek, Birgit Hüsing,

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

From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome

Ahmad Waseem, Yasmin Alam, Anand Lalli

Diana C. Blaydon, Sarah L. Etheridge, Janet M

Hongli Liu, M. D. , Ph. D. , Xiaofei Xu, M. D. , Ph. D. , Ting Han, M

The “Bald Mill Hill” Mutation in the Mouse Is Associated with an Abnormal, Mislocalized HR bmh Protein Maud-Virginie Brancaz-Bouvier, Eric J.G. Folco,

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

Somatic Mutations in NEK9 Cause Nevus Comedonicus

Aoi Nakano, Hajime Nakano, Sal LaForgia, Leena Pulkkinen, Jouni Uitto

Anna M. G. Pasmooij, Hendri H. Pas, Franciska C. L

Marcel F. Jonkman, Anna M. G. Pasmooij, Suzanne G. M. A

Fusako Sato, Gyula Soos, Charles Link, Kenzo Sato

Marie-Thérèse Leccia Journal of Investigative Dermatology

Epidermolysis Bullosa: Novel and De Novo Premature Termination Codon and Deletion Mutations in the Plectin Gene Predict Late-Onset Muscular Dystrophy

Mild Recessive Bullous Congenital Ichthyosiform Erythroderma due to a Previously Unidentified Homozygous Keratin 10 Nonsense Mutation Akiko Tsubota,

Claudia D. Andl, John R. Stanley Journal of Investigative Dermatology

A Mutation in SNAP29, Coding for a SNARE Protein Involved in Intracellular Trafficking, Causes a Novel Neurocutaneous Syndrome Characterized by Cerebral.

Anna M. G. Pasmooij, Hendri H. Pas, Franciska C. L

C-Terminus of Desmoyokin/AHNAK Protein is Responsible for its Translocation Between the Nucleus and Cytoplasm Zhuxiang Nie, Takashi Hashimoto Journal.

Genetic Heterogeneity in Erythrokeratodermia Variabilis: Novel Mutations in the Connexin Gene GJB4 (Cx30.3) and Genotype-Phenotype Correlations Gabriele.

Fatty Acid Transport Protein 1 Can Compensate for Fatty Acid Transport Protein 4 in the Developing Mouse Epidermis Meei-Hua Lin, Jeffrey H. Miner Journal.

Inhibition of Hair Follicle Growth by a Laminin-1 G-Domain Peptide, RKRLQVQLSIRT, in an Organ Culture of Isolated Vibrissa Rudiment1 Kazuhiro Hayashi,

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

Cryptic Splicing at a Non-Consensus Splice-Donor in a Patient with a Novel Mutation in the Plakophilin-1 Gene Peter M. Steijlen, Maurice A.M. van Steensel,

Connexin Mutations in Skin Disease and Hearing Loss

Functional Analysis of the Profilaggrin N-Terminal Peptide: Identification of Domains that Regulate Nuclear and Cytoplasmic Distribution David J. Pearton,

Volume 9, Issue 5, Pages (November 2017)

Compound Heterozygous TGM1 Mutations Including a Novel Missense Mutation L204Q in a Mild Form of Lamellar Ichthyosis Masashi Akiyama, Itsuro Matsuo

A Missense Mutation in the Zinc-Finger Domain of the Human Hairless Gene Underlies Congenital Atrichia in a Family of Irish Travellers Wasim Ahmad, Alan.

Expanding The Phenotypic Spectrum of Cx26 Disorders: Bart–Pumphrey Syndrome is Caused by a Novel Missense Mutation in GJB2 Gabriele Richard, Nkecha Brown,

Trangenic Misexpression of the Differentiation-Specific Desmocollin Isoform 1 in Basal Keratinocytes Frank Henkler, Molly Strom, Kathleen Mathers, Hayley.

Molecular Consequences of Deletion of the Cytoplasmic Domain of Bullous Pemphigoid 180 in a Patient with Predominant Features of Epidermolysis Bullosa.

Homozygous Mutations in the 5′ Region of the JUP Gene Result in Cutaneous Disease but Normal Heart Development in Children Rita M. Cabral, Lu Liu, Carol.

Abnormal Cornified Cell Envelope Formation in Mutilating Palmoplantar Keratoderma Unrelated to Epidermal Differentiation Complex Masashi Akiyama, Angela.

A Novel Recessive Connexin 31 (GJB3) Mutation in a Case of Erythrokeratodermia Variabilis Alessandro Terrinoni, Aida Leta, Cristina Pedicelli, Eleonora.

Barbara Marinari, Costanza Ballaro, Maranke I

PEX3 Is the Causal Gene Responsible for Peroxisome Membrane Assembly–Defective Zellweger Syndrome of Complementation Group G Kamran Ghaedi, Masanori.

Compound Heterozygosity for Non-Sense and Mis-Sense Mutations in Desmoplakin Underlies Skin Fragility/Woolly Hair Syndrome Neil V. Whittock, Hong Wan,

Multiple Epidermal Connexins are Expressed in Different Keratinocyte Subpopulations Including Connexin 31 Wei-Li Di, Elizabeth L. Rugg, Irene M. Leigh,

Epidermolytic Hyperkeratosis and Epidermolysis Bullosa Simplex Caused by Frameshift Mutations Altering the V2 Tail Domains of Keratin 1 and Keratin 5

Compound Heterozygosity for Novel Splice Site Mutations in the BPAG2/COL17A1 Gene Underlies Generalized Atrophic Benign Epidermolysis Bullosa Leena Pulkkinen,

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

The Expression of Vitamin D-Upregulated Protein 1 in Skin and its Interaction with Sciellin in Cultured Keratinocytes Marie-France Champliaud, Alain.

Alireza Haghighi, Claire A. Scott, Daniel S

Hirokatsu Yanagihori, Noritaka Oyama, Koichiro Nakamura, Fumio Kaneko

Alterations in Desmosome Size and Number Coincide with the Loss of Keratinocyte Cohesion in Skin with Homozygous and Heterozygous Defects in the Desmosomal.

A Mutation in the V1 Domain of K16 is Responsible for Unilateral Palmoplantar Verrucous Nevus Alessandro Terrinoni, Vincenzo De Laurenzi, Eleonora Candi,

Neil V. Whittock, Frances J. Smith, W.H. Irwin McLean

Truncation of CGI-58 Protein Causes Malformation of Lamellar Granules Resulting in Ichthyosis in Dorfman-Chanarin Syndrome Masashi Akiyama, Daisuke Sawamura,

A Novel GJB2 Mutation p.Asn54His in a Patient with Palmoplantar Keratoderma, Sensorineural Hearing Loss and Knuckle Pads Masashi Akiyama, Kaori Sakai,

Loss of Keratin 10 Leads to Mitogen-activated Protein Kinase (MAPK) Activation, Increased Keratinocyte Turnover, and Decreased Tumor Formation in Mice

Genetic Heterogeneity of KID Syndrome: Identification of a Cx30 Gene (GJB6) Mutation in a Patient with KID Syndrome and Congenital Atrichia Amy Y. Jan,

Zhimiao Lin, Quan Chen, Lei Shi, Mingyang Lee, Kathrin A

Matrix Metalloproteinase Inhibitor BB-3103 Unlike the Serine Proteinase Inhibitor Aprotinin Abrogates Epidermal Healing of Human Skin Wounds Ex Vivo1

Presentation transcript:

Missense Mutations in GJB2 Encoding Connexin-26 Cause the Ectodermal Dysplasia Keratitis-Ichthyosis-Deafness Syndrome Gabriele Richard, Fatima Rouan, Colin E. Willoughby, Nkecha Brown, Pil Chung, Markku Ryynänen, Ethylin Wang Jabs, Sherri J. Bale, John J. DiGiovanna, Jouni Uitto, Laura Russell The American Journal of Human Genetics Volume 70, Issue 5, Pages 1341-1348 (May 2002) DOI: 10.1086/339986 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical features of KID. A, Sharply demarcated, figurate outlined, red-brown hyperkeratotic plaques on the central face and outer rim of the ear (KID 05). B, Rarefied eyelashes and vascularizing keratitis (KID 05). C, Acanthosis of the skin with a heavy-grained leather appearance (KID 08). D, Diffuse palmar keratoderma with grainy surface (KID 03). E, Chronic Candida albicans onychia and paronychia with hypertrophy of distal digits, acanthosis, and hyperkeratosis of the skin (KID 09). The American Journal of Human Genetics 2002 70, 1341-1348DOI: (10.1086/339986) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutation analysis of GJB2 in eight individuals affected with sporadic disease and one multiplex family with KID. A, Sequence chromatograms of GJB2from unaffected (left panel) and affected (right panel) family members depicting the heterozygous transition 148G→A at codon 50 encoding asparagine instead of aspartic acid (D50N) observed in seven unrelated families with KID. B, Genotyping by automated pyrosequencing of biotinylated single-stranded DNA templates (Pyrosequencing) confirmed the presence of D50N in the affected patients (top row,pyrogram; bottom row, outcome as bar graph; both generated with Pyrosequencing software), whereas it was excluded from unaffected parents and siblings and from 54 control subjects. C and D, Sequence chromatograms of GJB2 from unaffected (left panel) and affected (middle panel) family members and the mutant allele (right panel) subcloned in the pcDNA2.1 vector (Invitrogen), showing (C) the heterozygous G→C transversion in codon 12, replacing glycine with arginine (G12R) in patient KID 08, and (D) the transition 50C→T, leading to substitution of serine 17 with phenylalanine (S17F), in one allele of patient KID 09. Individuals from whom DNA was obtained are marked with an asterisk (*). E, Schematic of the Cx26 polypeptide that depicts structural motifs and location of mutations in KID. NT = amino-terminus; M1–M4 = transmembrane domains 1–4, respectively; E1 and E2 = extracellular domains 1 and 2, respectively; CL = cytoplasmic loop; and CT = carboxy-terminus. The American Journal of Human Genetics 2002 70, 1341-1348DOI: (10.1086/339986) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Immunofluorescence (confocal microscopy) of normal (A, E, and I) and lesional (B–D, F–H, K, and L) skin in KID (KID 08) with Cx26, Cx43, and Cx30 antibodies. Immunohistochemical analyses were performed on 5-μm–thick sections of snap-frozen skin biopsies of normal control skin and lesional skin, as described elsewhere (Rouan et al. 2001). The primary monoclonal anti-Cx26 antibody (mouse [Zymed Laboratories; catalog number 33-5800]), which does not cross-react with Cx30, was detected with fluorescein-conjugated anti-mouse immunoglobin (green). The polyclonal anti-Cx43 and anti-Cx30 antibodies (rabbit [Zymed Laboratories]) were visualized with Texas Red–conjugated anti-rabbit immunoglobin (red). Areas of focal colocalization of Cx26 with either Cx30 or Cx43 are visualized in yellow. A, Normal epidermis, Cx26 (green). B–D, KID syndrome, Cx26 (green). Note the weak immunostaining of Cx26 in the granular cell layers (B, arrows) but strong expression in epithelial cells of sweat ducts (C) and outer root sheath of hair follicles (oblique cut) (D). E, Normal epidermis, Cx30 (red). F–H, KID syndrome, Cx30 (red) and Cx26 (green). Cx30 staining appears strictly compartmentalized with membranous and cytoplasmic staining in basal keratinocytes and punctate membrane staining of the upper differentiated cell layers. Note the focal colocalization of Cx26 and Cx30 in the granular epidermal layers (F, arrows), as well as in the sweat ducts (G) and hair follicles (H). I, Normal epidermis, Cx43 (red). K and L, KID syndrome, Cx43 (red) and Cx26 (green). Comparable expression of Cx43 throughout the epidermis in normal (I) and lesional skin (K) and colocalization of Cx26 with Cx43 in hair follicles (L). d = dermis; e = epidermis; sd = sweat duct; and hf = hair follicle. Scale bars = 10 μm. The American Journal of Human Genetics 2002 70, 1341-1348DOI: (10.1086/339986) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Immunofluorescence of normal human corneal epithelium with Cx26 (A), Cx30 (B), and Cx43 (C) antibodies. All connexin proteins showed, as expected, punctate staining at the cell membranes. A, Cx26 staining was relatively weak and was limited to the basal layer of the epithelium. B, Comparatively strong Cx30 expression throughout the basal and lower wing layers, sparing the superficial wing and squamous layers. C, Similar distribution of Cx43, with highest protein levels in the basal layer but staining extended throughout the wing layers. Scale bar = 10 μm. The American Journal of Human Genetics 2002 70, 1341-1348DOI: (10.1086/339986) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 5 Immunolocalization of wild-type Cx26 (A) and Cx26 S17F (B). HeLa cells expressing a tTA vector were stably transfected with Cx26-MYC-cDNA/pCEP-TetP vectors, grown in selective medium to >80% confluency, fixed, and stained with a monoclonal Cx26 antibody. A, WtCx26. B, Cx26 S17F. Arrows indicate plasma membrane staining at cell-cell contacts. Scale bar = 10 μm. The American Journal of Human Genetics 2002 70, 1341-1348DOI: (10.1086/339986) Copyright © 2002 The American Society of Human Genetics Terms and Conditions