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

Slides:

Advertisements

Similar presentations

Volume 158, Pages 1-7 (October 2017)

Advertisements

Figure 2. Co-expression of mutant proteins with wt cx26

Two novel mutations in PEO1 (Twinkle) gene associated with chronic external ophthalmoplegia Dario Ronchi, Elisa Fassone, Andreina Bordoni, Monica Sciacco,

A New Autosomal Recessive Form of Stickler Syndrome Is Caused by a Mutation in the COL9A1 Gene Guy Van Camp, Rikkert L. Snoeckx, Nele Hilgert, Jenneke.

Volume 141, Issue 6, Pages (December 2011)

Volume 7, Issue 10, Pages (October 2010)

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

A Homozygous Missense Mutation in TGM5 Abolishes Epidermal Transglutaminase 5 Activity and Causes Acral Peeling Skin Syndrome Andrew J. Cassidy, Maurice.

Volume 141, Issue 6, Pages (June 2010)

Genetic Diseases of Junctions

Mutations in the Transcription Factor Gene SOX18 Underlie Recessive and Dominant Forms of Hypotrichosis-Lymphedema-Telangiectasia Alexandre Irrthum,

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

Herlitz Junctional Epidermolysis Bullosa: Novel and Recurrent Mutations in the LAMB3 Gene and the Population Carrier Frequency Aoi Nakano, Ellen Pfendner,

Mutation Altering the miR-184 Seed Region Causes Familial Keratoconus with Cataract Anne E. Hughes, Declan T. Bradley, Malcolm Campbell, Judith Lechner,

Eija Siintola, Meral Topcu, Nina Aula, Hannes Lohi, Berge A

Valerie L. R. M. Verstraeten, Wolfgang Holnthoner, Maurice A. M

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

Targeted High-Throughput Sequencing Identifies Mutations in atlastin-1 as a Cause of Hereditary Sensory Neuropathy Type I Christian Guelly, Peng-Peng.

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

Ala 586 Asp mutation in androgen receptor disrupts transactivation function without affecting androgen binding Singh Rajender, Ph.D., Nalini J. Gupta,

Hyperglycosylation and Reduced GABA Currents of Mutated GABRB3 Polypeptide in Remitting Childhood Absence Epilepsy Miyabi Tanaka, Richard W. Olsen, Marco.

Mutations in ZDHHC9, Which Encodes a Palmitoyltransferase of NRAS and HRAS, Cause X-Linked Mental Retardation Associated with a Marfanoid Habitus F.

RSPO4 Is the Major Gene in Autosomal-Recessive Anonychia and Mutations Cluster in the Furin-Like Cysteine-Rich Domains of the Wnt Signaling Ligand R-spondin.

Novel Mutations in the BHD Gene and Absence of Loss of Heterozygosity in Fibrofolliculomas of Birt-Hogg-Dubé Patients Maurice A.M. van Steensel, Valerie.

Exome Sequencing Identifies SLCO2A1 Mutations as a Cause of Primary Hypertrophic Osteoarthropathy Zhenlin Zhang, Weibo Xia, Jinwei He, Zeng Zhang, Yaohua.

Mutations in Contactin-1, a Neural Adhesion and Neuromuscular Junction Protein, Cause a Familial Form of Lethal Congenital Myopathy Alison G. Compton,

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

Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome Wen-Bin He, Juan Du, Xiao-Wen Yang,

Alice E. Davidson, Ian D. Millar, Jill E

Identification of a Novel Mutation R42P in the Gap Junction Protein β-3 Associated with Autosomal Dominant Erythrokeratoderma Variabilis Amanda Wilgoss,

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

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

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,

A Novel Helix Termination Mutation in Keratin 10 in Annular Epidermolytic Ichthyosis, a Variant of Bullous Congenital Ichthyosiform Erythroderma Yasushi.

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

Gap Junctions: Basic Structure and Function

Heterozygous Mutations in AAGAB Cause Type 1 Punctate Palmoplantar Keratoderma with Evidence for Increased Growth Factor Signaling Elizabeth Pöhler,

ATM Mutations and Phenotypes in Ataxia-Telangiectasia Families in the British Isles: Expression of Mutant ATM and the Risk of Leukemia, Lymphoma, and.

Connexin Mutations in Skin Disease and Hearing Loss

A Novel 4 bp Deletion Mutation in the FALDH Gene Segregating in a Turkish Family with Sjögren–Larsson Syndrome Michel A.A.P. Willemsen, Peter M. Steijlen,

Taninee Sahakitrungruang, M. D. , Suttipong Wacharasindhu, M. D

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,

Mutations in ZDHHC9, Which Encodes a Palmitoyltransferase of NRAS and HRAS, Cause X-Linked Mental Retardation Associated with a Marfanoid Habitus F.

Semidominant Inheritance in Olmsted Syndrome

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

Ryan McDaniell, Daniel M. Warthen, Pedro A

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

L. Aravind, Eugene V. Koonin Current Biology

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

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

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

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

Volume 71, Issue 3, Pages (February 2007)

Clouston Syndrome Can Mimic Pachyonychia Congenita

Rare Mutations in XRCC2 Increase the Risk of Breast Cancer

Early Death from Cardiomyopathy in a Family with Autosomal Dominant Striate Palmoplantar Keratoderma and Woolly Hair Associated with a Novel Insertion.

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

Anthony M. Raizis, Martin M. Ferguson, David T. Nicholls, Derek W

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

Chromosomal Instability at Common Fragile Sites in Seckel Syndrome

Mutations in PRPS1, Which Encodes the Phosphoribosyl Pyrophosphate Synthetase Enzyme Critical for Nucleotide Biosynthesis, Cause Hereditary Peripheral.

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.

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

Conversion and Compensatory Evolution of the γ-Crystallin Genes and Identification of a Cataractogenic Mutation That Reverses the Sequence of the Human.

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

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.

A Phenotype Resembling the Clouston Syndrome with Deafness Is Associated with a Novel Missense GJB2 Mutation Maurice A.M. van Steensel, Peter M. Steijlen,

Presentation transcript:

A Novel Missense Mutation in the Second Extracellular Domain of GJB2, p.Ser183Phe, Causes a Syndrome of Focal Palmoplantar Keratoderma with Deafness Eugene A. de Zwart-Storm, Michel van Geel, Pierre A.F.A. van Neer, Peter M. Steijlen, Patricia E. Martin, Maurice A.M. van Steensel The American Journal of Pathology Volume 173, Issue 4, Pages 1113-1119 (October 2008) DOI: 10.2353/ajpath.2008.080049 Copyright © 2008 American Society for Investigative Pathology Terms and Conditions

Figure 1 Presence of the mutation within the index family. A: Pedigree of the family, with the filled symbols representing the affected members and the proband indicated by an arrow. B: Restriction analysis with NciI; mutation present in the mother and daughter (lanes 1 and 3, respectively; 535, 440, 318, and 122 bp), not in the father or a son (lanes 2 and 4, respectively; 535, 318, and 122 bp). The American Journal of Pathology 2008 173, 1113-1119DOI: (10.2353/ajpath.2008.080049) Copyright © 2008 American Society for Investigative Pathology Terms and Conditions

Figure 2 Clinical phenotype of the index patient. A: Diffuse, flat, hyperkeratotic translucent plaques were present on the palms, in particular on the border of the thenar and wrist. B: Close-up view of the mild palmar hyperkeratosis. C: Hyperkeratotic plaques were seen in areas exposed to mechanical stress, such as heels, balls of feet, knuckles, and wrists, sometimes in the form of knuckle pads. D: Hyperkeratotic plaques (knuckle pads) on the toes. E: Mild diffuse plantar hyperkeratosis. F: Close-up of the plantar surface, where areas with hyperkeratosis are clearly visible. Note that the plaques seem to actually be formed by confluence of smaller hyperkeratotic papules. The American Journal of Pathology 2008 173, 1113-1119DOI: (10.2353/ajpath.2008.080049) Copyright © 2008 American Society for Investigative Pathology Terms and Conditions

Figure 3 Pronounced sensory hearing loss, in particular for higher frequencies (vertical: decibels; horizontal: the frequency in KHz). Air conduction: cross/round marks; bone conduction: triangles, arrows pointing downwards indicate the loudest tone was not heard). The curves of a normal-hearing person are almost horizontal at ∼10 to 15 decibels. The American Journal of Pathology 2008 173, 1113-1119DOI: (10.2353/ajpath.2008.080049) Copyright © 2008 American Society for Investigative Pathology Terms and Conditions

Figure 4 GJB2 sequence chromatograms of an unaffected family member (Wt) and a patient (Mt) at the mutated location (arrow). The American Journal of Pathology 2008 173, 1113-1119DOI: (10.2353/ajpath.2008.080049) Copyright © 2008 American Society for Investigative Pathology Terms and Conditions

Figure 5 Results of GJB2/EGFP fusion protein (green: Cx26wt/mt, red: stably expressed Cx26wt) detection in HeLa Ohio cells. A: Gap junction plaque formation by wild-type GJB2/EGFP fusion protein (arrows). B: Some gap junction plaque formation is visible with p.Ser183Phe-GJB2/EGFP mutant fusion protein (arrows), but most of the protein accumulates in the cytoplasm and endoplasmic reticulum. C: Co-localization of stably expressed Cx26wt (red) and transfected Cx26wt (green) at the membrane and in intercellular gap junction plaques (merge = yellow, arrow gap junction plague). D: There is no rescue of the mutant protein with Cx26wt; its primarily cytoplasmatic distribution is suggestive for ER localization. Note that most of the wild-type protein co-localizes with the mutant, suggesting a dominant-negative effect on transport of the latter (arrows, gap junction plaques). The American Journal of Pathology 2008 173, 1113-1119DOI: (10.2353/ajpath.2008.080049) Copyright © 2008 American Society for Investigative Pathology Terms and Conditions

Figure 6 HeLa Ohio cells (marked with an asterisk) transfected with GJB2/EGFP, p.Ser183Phe-GJB2/EGFP, or untransfected, loaded with CM-DiI (red) and calcein (MW622 Da, charge −4) parachuted onto a monolayer of HeLa Ohio cells stably expressing Cx26wt. A: HeLa Ohio cells transfected with GJB2/EGFP show transfer of calcein to a monolayer of HeLa Ohio cells stably expressing Cx26wt. B: HeLa Ohio cells transfected with p.Ser183Phe-GJB2/EGFP show transfer of calcein to a monolayer of HeLa Ohio cells stably expressing Cx26wt. C: HeLa Ohio cells, untransfected, show no transfer of calcein to a monolayer of HeLa Ohio cells stably expressing Cx26wt. The American Journal of Pathology 2008 173, 1113-1119DOI: (10.2353/ajpath.2008.080049) Copyright © 2008 American Society for Investigative Pathology Terms and Conditions

Figure 7 Conservation throughout species and within connexins of E2 domain sequence. No Cx preface is Homo sapiens. Abbreviations: Mmul, Macaca mulatta; Bt, Bos taurus; Cf, Canis familiaris; Ec, Equus caballus; Mm, Mus musculus; Md, Monodelphis domestica; Oa, Ornithorhynchus anatinus; Gg, Gallus gallus; Xl, Xenopus laevis. The American Journal of Pathology 2008 173, 1113-1119DOI: (10.2353/ajpath.2008.080049) Copyright © 2008 American Society for Investigative Pathology Terms and Conditions