Xeroderma Pigmentosum-Variant Patients from America, Europe, and Asia

Slides:

Advertisements

Similar presentations

A Novel XPA Gene Mutation and its Functional Analysis in a Japanese Patient with Xeroderma Pigmentosum Group A Miki Tanioka, Arief Budiyant, Takahiro.

Advertisements

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

Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy Yu-jin Qu, Jin-li Bai, Yan-yan.

Novel Splice Variants of IL-33: Differential Expression in Normal and Transformed Cells Hidetoshi Tsuda, Mayumi Komine, Masaru Karakawa, Takafumi Etoh,

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

Undifferentiated Small Round Cell Sarcomas with Rare EWS Gene Fusions

Combination of a Novel Frameshift Mutation (1929delCA) and a Recurrent Nonsense Mutation (W610X) of the LAMB3 Gene in a Japanese Patient with Herlitz.

Structural and Functional Mutations of the Perlecan Gene Cause Schwartz-Jampel Syndrome, with Myotonic Myopathy and Chondrodysplasia Eri Arikawa-Hirasawa,

A Stop Codon in Xeroderma Pigmentosum Group C Families in Turkey and Italy: Molecular Genetic Evidence for a Common Ancestor Engin M. Gozukara, Sikandar.

Molecular Mechanisms of Junctional Epidermolysis Bullosa: Col15 Domain Mutations Decrease the Thermal Stability of Collagen XVII Laura Väisänen, Cristina.

Rose-Anne Romano, Barbara Birkaya, Satrajit Sinha

Severe Palmo-Plantar Hyperkeratosis in Dowling–Meara Epidermolysis Bullosa Simplex Caused by a Mutation in the Keratin 14 Gene (KRT14) Carrie S. Shemanko

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

Volume 54, Issue 3, Pages (September 1998)

Psoriasis Upregulated Phorbolin-1 Shares Structural but not Functional Similarity to the mRNA-Editing Protein Apobec-1 Peder Madsen, Julio E. Celis,

Kyu-Seon Oh, Steffen Emmert, Deborah Tamura, John J

Steffen Emmert, Hanoch Slor, David B. Busch, Sima Batko, Roberta B

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

Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease Alberto Auricchio, Paola.

Analysis of Rare APC Variants at the mRNA Level

Kenneth H. Kraemer, John J. DiGiovanna

Elizabeth R. Heller, Sikandar G

Splice Site and Deletion Mutations in Keratin (KRT1 and KRT10) Genes: Unusual Phenotypic Alterations in Scandinavian Patients with Epidermolytic Hyperkeratosis

Clinical, Cellular, and Molecular Features of an Israeli Xeroderma Pigmentosum Family with a Frameshift Mutation in the XPC Gene: Sun Protection Prolongs.

A Rare Case of Hypohidrotic Ectodermal Dysplasia Caused by Compound Heterozygous Mutations in the EDAR Gene Yutaka Shimomura, Nobuyuki Sato, Akinori.

RNA-Guided Genome Editing in Plants Using a CRISPR–Cas System

Laminin-5 Mutational Analysis in an Italian Cohort of Patients with Junctional Epidermolysis Bullosa Patrizia Posteraro, Naomi De Luca, Guerrino Meneguzzi,

Characterization of Three XPG-Defective Patients Identifies Three Missense Mutations that Impair Repair and Transcription Annika Schäfer, Steffen Schubert,

A Homozygous Nonsense Mutation in Type XVII Collagen Gene (COL17A1) Uncovers an Alternatively Spliced mRNA Accounting for an Unusually Mild Form of Non-Herlitz.

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

Transcriptional Regulation of ATP2C1 Gene by Sp1 and YY1 and Reduced Function of its Promoter in Hailey–Hailey Disease Keratinocytes Hiroshi Kawada,

A Novel XPA Gene Mutation and its Functional Analysis in a Japanese Patient with Xeroderma Pigmentosum Group A Miki Tanioka, Arief Budiyant, Takahiro.

Sikandar G. Khan, Harvey L

A Newly Identified Patient with Clinical Xeroderma Pigmentosum Phenotype has a Non- Sense Mutation in the DDB2 Gene and Incomplete Repair in (6-4) Photoproducts

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

Decreased Extracellular-Signal-Regulated Kinase and Increased Stress-Activated MAP Kinase Activities in Aged Human Skin In Vivo Jin Ho Chung, Sewon Kang,

A Novel Point Mutation Affecting the Tyrosine Kinase Domain of the TRKA Gene in a Family with Congenital Insensitivity to Pain with Anhidrosis Shinichi.

Neil V. Whittock, Gabrielle H. S. Ashton, Patricia J. C

Human Elastase 1: Evidence for Expression in the Skin and the Identification of a Frequent Frameshift Polymorphism Ulvi Talas, John Dunlop, Sahera Khalaf,

Founder Mutations in Xeroderma Pigmentosum

Feras M. Hantash, Arlene Rebuyon, Mei Peng, Joy B

Regulation of the Expression of Peptidylarginine Deiminase Type II Gene (PADI2) in Human Keratinocytes Involves Sp1 and Sp3 Transcription Factors Sijun.

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.

Deletion of PREPL, a Gene Encoding a Putative Serine Oligopeptidase, in Patients with Hypotonia-Cystinuria Syndrome Jaak Jaeken, Kevin Martens, Inge.

Emmanuelle Bitoun, Stéphane Chavanas, Alan D

Volume 58, Issue 2, Pages (August 2000)

Opitz G/BBB Syndrome in Xp22: Mutations in the MID1 Gene Cluster in the Carboxy- Terminal Domain Karin Gaudenz, Erich Roessler, Nandita Quaderi, Brunella.

A Novel Complex Insertion/Deletion Mutation in the XPC DNA Repair Gene Leads to Skin Cancer in an Iraqi Family Steffen Emmert, Tino Wetzig, Kyoko Imoto,

Dan Yu, Rongdiao Liu, Geng Yang, Qiang Zhou Cell Reports

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

A Usual Frameshift and Delayed Termination Codon Mutation in Keratin 5 Causes a Novel Type of Epidermolysis Bullosa Simplex with Migratory Circinate Erythema

Wook Lew Journal of Investigative Dermatology

Transcriptional Control of SLC26A4 Is Involved in Pendred Syndrome and Nonsyndromic Enlargement of Vestibular Aqueduct (DFNB4) Tao Yang, Hilmar Vidarsson,

Identification of Transglutaminase 3 Splicing Isoforms

Volume 57, Issue 6, Pages (June 2000)

Identification of Recurrent Mutations in the ARS (Component B) Gene Encoding SLURP-1 in Two Families with Mal de Meleda Kimberley Morine Ward, Jülide.

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

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

Volume 93, Issue 1, Pages (April 1998)

Identification of Skn-1n, a Splice Variant Induced by High Calcium Concentration and Specifically Expressed in Normal Human Keratinocytes Koji Nakajima,

Bart A. Jessen, Marjorie A. Phillips, Robert H. Rice

Two Exon-Skipping Mutations as the Molecular Basis of Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria) Ken L. Chambliss, Debra.

Extracellular Matrix Protein 1 Gene (ECM1) Mutations in Lipoid Proteinosis and Genotype-Phenotype Correlation Takahiro Hamada, Vesarat Wessagowit, Andrew.

Exon Tethering in Transcription by RNA Polymerase II

Is Screening of the Candidate Gene Necessary in Unrelated Partners of Members of Families with Herlitz Junctional Epidermolysis Bullosa? Alfred Klausegger,

Mutations in PTPRQ Are a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB84 and Associated with Vestibular Dysfunction Margit Schraders,

Hermansky-Pudlak Syndrome Type 3 in Ashkenazi Jews and Other Non–Puerto Rican Patients with Hypopigmentation and Platelet Storage-Pool Deficiency Marjan.

Familial Porphyria Cutanea Tarda: Characterization of Seven Novel Uroporphyrinogen Decarboxylase Mutations and Frequency of Common Hemochromatosis Alleles

Exon Skipping in IVD RNA Processing in Isovaleric Acidemia Caused by Point Mutations in the Coding Region of the IVD Gene Jerry Vockley, Peter K. Rogan,

Identification of a New Splice Form of the EDA1 Gene Permits Detection of Nearly All X- Linked Hypohidrotic Ectodermal Dysplasia Mutations Alex W. Monreal,

Presentation transcript:

Xeroderma Pigmentosum-Variant Patients from America, Europe, and Asia Hiroki Inui, Kyu-Seon Oh, Carine Nadem, Takahiro Ueda, Sikandar G. Khan, Ahmet Metin, Engin Gozukara, Steffen Emmert, Hanoch Slor, David B. Busch, Carl C. Baker, John J. DiGiovanna, Deborah Tamura, Cornelia S. Seitz, Alexei Gratchev, Wen Hao Wu, Kee Yang Chung, Hye Jin Chung, Esther Azizi, Roger Woodgate, Thomas D. Schneider, Kenneth H. Kraemer Journal of Investigative Dermatology Volume 128, Issue 8, Pages 2055-2068 (August 2008) DOI: 10.1038/jid.2008.48 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical appearance of XP-V patients. Family A: (a) XP31BE, 60 year Caucasian man had full-thickness skin removed from his face as a teenager because of multiple skin cancers. This skin was replaced with sun-protected skin from his abdomen and has been free of cancers ever since. He had BCC, SCC, and melanomas on non-grafted skin of his head and upper extremities. Family C: (b) C-1, XP71TMA, 8-year-old Turkish boy, had SCC. (c) C-2, XP70TMA, 17-year-old sister of XP71TMA, had SCC and BCC. (d) C-3, XP98TMA, 26-year-old sister of XP71TMA, had a large SCC on her left cheek. Family D: (e) D-1, XP91TMA, a 10-year-old Turkish man, had no skin cancers. (f) D-2, XP92TMA, brother of XP91TMA, died at age 22 years of metastasis of the SCC on his lip. Family F: (g) F-1, XP161BE, a 46-year-old Caucasian woman with multiple skin BCCs and melanomas. (h) F-2, XP164BE, 52-year-old sister of XP161BE, had multiple BCCs, SCCs, and melanomas. Family G: (i) XP3GO, a 30-year-old German man with multiple BCCs, SCCs, and melanomas. Family I: (j) XP224BE, a 31-year-old Caucasian woman, had multiple BCCs and melanomas. Journal of Investigative Dermatology 2008 128, 2055-2068DOI: (10.1038/jid.2008.48) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Post-UV host cell reactivation assay showing normal DNA repair in XP-V cells. UV-treated or control unirradiated luciferase containing plasmid was transfected into cells from normal (AG5186) (light gray bar), XP-C (XP108DC) (dark gray bar), and putative XP-V donors (XP31BE, XP38BE, XP164BE, XP70TMA, XP92TMA, XP3GO, XP224BE, and XP10TA) (open bars). Two days later luciferase activity was measured. The relative luciferase activity of the UV treated to the control plasmid reflects repair activity of the cells. The XP-C cell had low activity and the putative XP-V cells had repair activity in the normal range. The mean±SEM of triplicate experiments is shown. Journal of Investigative Dermatology 2008 128, 2055-2068DOI: (10.1038/jid.2008.48) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Semi-quantitative estimation of polη and polι protein in XP and normal fibroblasts. Normal and putative XP-V cells were assayed by IP-Western blotting of whole-cell extracts. (a) Polη protein and (b) polι protein. Journal of Investigative Dermatology 2008 128, 2055-2068DOI: (10.1038/jid.2008.48) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Sequence analysis of family A. (a) Genomic DNA of XP31BE shows change of G to C at exon 6 splice donor site (arrows). There is a single curve in the uncloned DNA, indicating homozygous or hemizygous mutation. (b) RT-PCR using RNA from XP31BE with forward primer C504F (in exon 5) and reverse primer C892R (spanning the exon 8/7 junction) showed a single 388-bp band in normal cells and two bands (arrows) at 284 and 346bp in XP31BE cells. The diagram indicates deletion of the entire 104bp of exon 6 in the type-I splice variant and partial deletion (42bp) of exon 6 in the type-II splice variant. (c) PCR-RFLP assay for family A. The G-to-C mutation creates a new DdeI restriction site. The gel shows genomic DNA from the father, XP31BE, mother, and a normal donor. + Indicates DdeI treatment. The arrows indicate 63 and 54-bp bands of digested DNA. * Indicates the normal-size band. Journal of Investigative Dermatology 2008 128, 2055-2068DOI: (10.1038/jid.2008.48) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Analysis of genomic DNA of families C and D. The C454T mutation in exon 4 creates a new DdeI restriction site. DNA from a normal donor, affected siblings XP70TMA, XP71TMA, XP98TMA, and their mother (XPH95TMA) in family C, and affected siblings XP91TMA and XP92TMA in family D were separated on 3% agarose gel. + Indicates DNA digested with DdeI. The digested DNA showed two bands of 92 and 132bp (arrows). * Indicates the normal-size band. Journal of Investigative Dermatology 2008 128, 2055-2068DOI: (10.1038/jid.2008.48) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Sequence analysis of families E and F. (a) Genomic DNA from XP38BE in family E shows an insertion of a G in exon 10. There is a single sequence following the insertion indicating that the DNA is homozygous or hemizygous for this frameshift mutation. (b) PCR-RFLP assay of family E. The insertion of G creates a new BsII site in the genomic DNA. Genomic DNA from a normal donor, patients XP38BE, XP39BE, and their mother, XPH253BE, was run on a gel. + Indicates BsII treatment. The 105 and 248-bp bands in the digested DNA are indicated by arrows. * Indicates the normal-size band. (c) PCR-RFLP analysis for family F. Genomic DNA from XP164BE, XP161BE, the husband, son, daughter, mother, and father of XP161BE was run on a gel. + Indicates BsII treatment. The 105 and 248-bp bands in the digested DNA are indicated by arrows. * Indicates the normal size band. Journal of Investigative Dermatology 2008 128, 2055-2068DOI: (10.1038/jid.2008.48) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Mutation spectrum and predicted proteins in XP-V cells. The top line shows the 11 exons of POLH genomic sequence on chromosome 6 as filled rectangles. The location of frameshift, nonsense, and missense mutations in each allele for the cells studied is shown above the line and the splice site mutations are shown below the line. The second line shows the mRNA with the ATG initiation codon in exon 2 and the TAG stop codon in exon 11. The 713-amino-acid pol-η protein is shown in the third line. The N-terminal 400 amino acids are highly conserved in Y-family polymerases, and contain the catalytic domain of the polymerase. There is a nuclear localization signal located at amino acids 682–698 (NLS). The C-terminal region from amino acids 628–662 contains a C2H2 zinc finger that is involved in DNA-binding ubiquitin. A PCNA-binding site is located at the extreme C-terminus of the protein. The bottom portion of the figure shows the predicted size of the protein from each allele or splice variant form from the XP-V patients and the description of the mutation at the cDNA and protein level. PCNA, proliferating-cell nuclear antigen. Journal of Investigative Dermatology 2008 128, 2055-2068DOI: (10.1038/jid.2008.48) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions