The Experts below are selected from a list of 31719 Experts worldwide ranked by ideXlab platform
K Stephens - One of the best experts on this subject based on the ideXlab platform.
-
a common Keratin 5 gene mutation in epidermolysis bullosa simplex weber cockayne
Journal of Investigative Dermatology, 1995Co-Authors: Pamela Ehrlich, Virginia P Sybert, Anne Spencer, K StephensAbstract:The Weber-Cockayne subtype of epidermolysis bullosa simplex is an inherited skin-fragility disorder characterized by basal Keratinocyte lysis and epidermal blistering confined primarily to the hands and feet. The disorder results from a mutation in either the Keratin 5 or Keratin 14 gene, which encode the peptide components of the obligate heterodimeric Keratin intermediate filaments of the basal cell. We have determined that a T → G substitution mutation in Keratin 5, which results in a Ile → Ser change codon 161, is common among patients with the Weber-Cockayne disease variant, accounting for six of 13 cases tested. The observed high frequency of this mutation may result from either a mutational hot spot or a founder effect, The potential utility of this common mutation in confirming disease status in some at-risk individual is discussed.
-
A Common Keratin 5 Gene Mutation in Epidermolysis Bullosa Simplex–Weber-Cockayne
The Journal of investigative dermatology, 1995Co-Authors: Pamela Ehrlich, Virginia P Sybert, Anne Spencer, K StephensAbstract:The Weber-Cockayne subtype of epidermolysis bullosa simplex is an inherited skin-fragility disorder characterized by basal Keratinocyte lysis and epidermal blistering confined primarily to the hands and feet. The disorder results from a mutation in either the Keratin 5 or Keratin 14 gene, which encode the peptide components of the obligate heterodimeric Keratin intermediate filaments of the basal cell. We have determined that a T-->G substitution mutation in Keratin 5, which results in a Ile-->Ser change at codon 161, is common among patients with the Weber-Cockayne disease variant, accounting for six of 13 cases tested. The observed high frequency of this mutation may result from either a mutational hot spot or a founder effect. The potential utility of this common mutation in confirming disease status in some at-risk individual is discussed.
-
Epidermolysis bullosa simplex: a Keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function.
American journal of human genetics, 1995Co-Authors: K Stephens, Pamela Ehrlich, Robert J Livingston, Lynne T Smith, A Zlotogorski, Ellen M. Wijsman, Virginia P SybertAbstract:Abstract To explore the relationship between abnormal Keratin molecules, 10-nm intermediate filament (IF) organization, and epidermal fragility and blistering, we sought to determine the functional consequences of homozygosity for a dominant Keratin defect. We describe a family with an autosomal dominant skin-blistering disorder, epidermolysis bullosa simplex, Koebner subtype (EBS-K), that has a novel point mutation, occurring in the Keratin 5 gene (KRT5), that predicts the substitution of an evolutionarily conserved lysine by an asparagine residue (K173N). Unlike previous heterozygous mutations located within the initial segment of domain 1A of Keratin molecules, K173N heterozygosity did not result in severe disease or clumping of Keratin filaments. One family member was found to be homozygous for the K173N allele, having inherited it from each of her affected first-cousin parents. Despite a lack of normal Keratin 5 molecules, and an effective doubling of abnormal molecules, available for heterodimerization with Keratin 14 during IF formation, there were no significant differences in the clinical severity or the ultrastructural organization of the Keratin IF cytoskeleton of the homozygous individual. These data demonstrate that the K173N mutation behaves as a fully dominant allele and indicate that a limited number of abnormal Keratin molecules are sufficient to impair cytoskeletal function and elicit epidermal fragility and blistering.
-
A homozygous mutation in Keratin 5 is a fully dominant allele responsible for epidermolysis bullosa simplex
American Journal of Human Genetics, 1994Co-Authors: K Stephens, Lynne T Smith, Pamela EhrlichAbstract:Molecular, ultrastructural, and clinical analysis of a large family with epidermolysis bullosa simplex (EBS) and multiple consanguineous marriages has identified one affected individual who inherited defective Keratin 5 genes from both of her affected parents. EBS are skin blistering disorders caused by abnormal Keratin filament assembly or function due to a mutation in either of the two structural proteins Keratin 5 or Keratin 14. Linkage analysis with DNA markers near each Keratin gene demonstrated that the defect in this family mapped near Keratin 5 (K5) with a LOD score of 7.60, {theta}=0.0 for the proximal marker D12S14. Sequencing of the K5 gene identified an Asn substitution of a highly conserved Lys at codon 173 in the 5{prime} end of the central rod domain. The mutation was found in 33 affected family members but not in 5 unaffected members or 25 unrelated, unaffected individuals. Both linkage and sequence analysis verified that one affected individual was homozygous for the K5 mutation. In this family, clinical examination and analysis of epidermal ultrastructure by electron microscopy were consistent with the Koebner subtype of EBS. Despite the absence of any normal K5 protein in the skin, the clinical and ultrastructural phenotypes of the homozygous individualmore » did not differ significantly from those of affected heteozygous relatives. This K5 mutation is a fully dominant allele.« less
Pamela Ehrlich - One of the best experts on this subject based on the ideXlab platform.
-
a common Keratin 5 gene mutation in epidermolysis bullosa simplex weber cockayne
Journal of Investigative Dermatology, 1995Co-Authors: Pamela Ehrlich, Virginia P Sybert, Anne Spencer, K StephensAbstract:The Weber-Cockayne subtype of epidermolysis bullosa simplex is an inherited skin-fragility disorder characterized by basal Keratinocyte lysis and epidermal blistering confined primarily to the hands and feet. The disorder results from a mutation in either the Keratin 5 or Keratin 14 gene, which encode the peptide components of the obligate heterodimeric Keratin intermediate filaments of the basal cell. We have determined that a T → G substitution mutation in Keratin 5, which results in a Ile → Ser change codon 161, is common among patients with the Weber-Cockayne disease variant, accounting for six of 13 cases tested. The observed high frequency of this mutation may result from either a mutational hot spot or a founder effect, The potential utility of this common mutation in confirming disease status in some at-risk individual is discussed.
-
A Common Keratin 5 Gene Mutation in Epidermolysis Bullosa Simplex–Weber-Cockayne
The Journal of investigative dermatology, 1995Co-Authors: Pamela Ehrlich, Virginia P Sybert, Anne Spencer, K StephensAbstract:The Weber-Cockayne subtype of epidermolysis bullosa simplex is an inherited skin-fragility disorder characterized by basal Keratinocyte lysis and epidermal blistering confined primarily to the hands and feet. The disorder results from a mutation in either the Keratin 5 or Keratin 14 gene, which encode the peptide components of the obligate heterodimeric Keratin intermediate filaments of the basal cell. We have determined that a T-->G substitution mutation in Keratin 5, which results in a Ile-->Ser change at codon 161, is common among patients with the Weber-Cockayne disease variant, accounting for six of 13 cases tested. The observed high frequency of this mutation may result from either a mutational hot spot or a founder effect. The potential utility of this common mutation in confirming disease status in some at-risk individual is discussed.
-
Epidermolysis bullosa simplex: a Keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function.
American journal of human genetics, 1995Co-Authors: K Stephens, Pamela Ehrlich, Robert J Livingston, Lynne T Smith, A Zlotogorski, Ellen M. Wijsman, Virginia P SybertAbstract:Abstract To explore the relationship between abnormal Keratin molecules, 10-nm intermediate filament (IF) organization, and epidermal fragility and blistering, we sought to determine the functional consequences of homozygosity for a dominant Keratin defect. We describe a family with an autosomal dominant skin-blistering disorder, epidermolysis bullosa simplex, Koebner subtype (EBS-K), that has a novel point mutation, occurring in the Keratin 5 gene (KRT5), that predicts the substitution of an evolutionarily conserved lysine by an asparagine residue (K173N). Unlike previous heterozygous mutations located within the initial segment of domain 1A of Keratin molecules, K173N heterozygosity did not result in severe disease or clumping of Keratin filaments. One family member was found to be homozygous for the K173N allele, having inherited it from each of her affected first-cousin parents. Despite a lack of normal Keratin 5 molecules, and an effective doubling of abnormal molecules, available for heterodimerization with Keratin 14 during IF formation, there were no significant differences in the clinical severity or the ultrastructural organization of the Keratin IF cytoskeleton of the homozygous individual. These data demonstrate that the K173N mutation behaves as a fully dominant allele and indicate that a limited number of abnormal Keratin molecules are sufficient to impair cytoskeletal function and elicit epidermal fragility and blistering.
-
A homozygous mutation in Keratin 5 is a fully dominant allele responsible for epidermolysis bullosa simplex
American Journal of Human Genetics, 1994Co-Authors: K Stephens, Lynne T Smith, Pamela EhrlichAbstract:Molecular, ultrastructural, and clinical analysis of a large family with epidermolysis bullosa simplex (EBS) and multiple consanguineous marriages has identified one affected individual who inherited defective Keratin 5 genes from both of her affected parents. EBS are skin blistering disorders caused by abnormal Keratin filament assembly or function due to a mutation in either of the two structural proteins Keratin 5 or Keratin 14. Linkage analysis with DNA markers near each Keratin gene demonstrated that the defect in this family mapped near Keratin 5 (K5) with a LOD score of 7.60, {theta}=0.0 for the proximal marker D12S14. Sequencing of the K5 gene identified an Asn substitution of a highly conserved Lys at codon 173 in the 5{prime} end of the central rod domain. The mutation was found in 33 affected family members but not in 5 unaffected members or 25 unrelated, unaffected individuals. Both linkage and sequence analysis verified that one affected individual was homozygous for the K5 mutation. In this family, clinical examination and analysis of epidermal ultrastructure by electron microscopy were consistent with the Koebner subtype of EBS. Despite the absence of any normal K5 protein in the skin, the clinical and ultrastructural phenotypes of the homozygous individualmore » did not differ significantly from those of affected heteozygous relatives. This K5 mutation is a fully dominant allele.« less
Jouni Uitto - One of the best experts on this subject based on the ideXlab platform.
-
Epidermolysis Bullosa Simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date
European journal of dermatology : EJD, 2006Co-Authors: Daniel L. Shurman, Jouni Uitto, Jacqueline Losi-sasaki, Ronald E. Grimwood, Sirpa Kivirikko, Elizabeth H. Tichy, Gabriele RichardAbstract:Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP), characterized by trauma-induced blisters, distinct pigmentary changes of the trunk and extremities, and acral hyperkeratotic papules, is almost exclusively caused by a common KRT5 missense mutation affecting the V1 region of Keratin 5. We studied the first Hispanic family, the largest single generation of affected family members in which 5 out of 10 siblings inherited EBS-MP from their affected father, as well a second large pedigree, the first reported of Finnish ancestry. In both families, the heterozygous transition mutation 74C-->T of the Keratin 5 gene, which results in amino acid substitution P25L, completely co-segregated with the EBS-MP phenotype.
-
Epidermolytic hyperkeratosis and epidermolysis bullosa simplex caused by frameshift mutations altering the v2 tail domains of Keratin 1 and Keratin 5.
Journal of Investigative Dermatology, 2003Co-Authors: Eli Sprecher, Gil Yosipovitch, Reuven Bergman, Dan Ciubutaro, Margarita Indelman, Ellen Pfendner, Leok C. Goh, Christopher J. Miller, Jouni Uitto, Gabriele RichardAbstract:The cytoskeleton of epithelial cells is formed by heteropolymeric Keratin proteins characterized by a central α-helical rod flanked by nonhelical head and tail domains of variable sequence. Most mutations described in 18 distinct Keratins disrupt highly conserved regions at the boundaries of the rod, which have been recognized as zones of overlap during Keratin alignment and assembly into intermediate filaments. We recently reported the first mutation located in a Keratin tail domain (V2) in ichthyosis hystrix Curth–Macklin. In this study, we report two novel frameshift mutations that are predicted to alter the tail of Keratin 1 or Keratin 5, leading to an atypical form of epidermolytic hyperkeratosis and a mild form of epidermolysis bullosa simplex, respectively. Mutation analysis of the patient with epidermolytic hyperkeratosis revealed a de novo heterozygous nucleotide insertion (1752insG) in exon 9 of KRT1, predicted to result in an aberrant 69 residue Keratin 1 tail. In the patient with mild epidermolysis bullosa simplex, we identified a single nucleotide deletion (1635delG) in exon 9 of KRT5 leading to frameshift and translation of an abnormal V2 domain, 35 amino acids longer than the native Keratin 5 tail. Our results, together with previous observations, establish the existence of a subgroup of Keratin disorders due to frameshift mutations altering the Keratin tail domains that are characterized by phenotypic heterogeneity.
-
Identification of a leucine-to-proline mutation in the Keratin 5 gene in a family with the generalized Köbner type of epidermolysis bullosa simplex.
Human mutation, 1993Co-Authors: Wei Dong, Markku Ryynanen, Jouni UittoAbstract:We have previously reported linkage of a large Finnish family with the generalized (Kobner) type of epidermolysis bullosa simplex to chromosome 12q in the region containing the type II Keratin gene cluster (Ryynanen et al., Am J Human Genet 49:978–984, 1991). In this study, we examined the possibility that Keratin 5, the type II Keratin expressed in the basal Keratinocytes, harbors the mutation in this family. Nucleotide sequencing revealed a T-to-C transition within exon 7 of the Keratin 5 gene in the affected individuals of the family, while the unaffected individuals showed no evidence of C. The presence of the T-to-C transition in the affected individuals was confirmed by restriction enzyme digestion analysis with Ncil endonuclease, as well as with PCR amplification of specific alleles (PASA) analysis. The PASA analysis also indicated that the mutated allele was not found among the 100 alleles tested within the general Finnish population indicating that the mutated allele is not a common polymhism. Furthermore, the mutated allele was not present in nine individuals representing three different EBS families of Finnish origin. The T-to-C transition at the nucleotide level resulted in substitution of a leucine by a proline at the amino acid level, and the substitution affected a leucine residue which was invariant among eight different human Keratins in a highly conserved segment at the carboxy-terminal region of the Keratin 5 polypeptide. In analogy with previously elucidated mutations in Keratins expressed in basal Keratinocytes, it is highly probable that the leucine-to-proline substitution in the Keratin 5 gene, which completely cosegregated with the clinical phenotype, is the underlying cause of the blistering tendency in this family with EBS of the generalized, Kobner type. © 1993 Wiley-Liss, Inc.
Virginia P Sybert - One of the best experts on this subject based on the ideXlab platform.
-
expression of a truncated Keratin 5 may contribute to severe palmar plantar hyperkeratosis in epidermolysis bullosa simplex patients
Journal of Investigative Dermatology, 2001Co-Authors: Robert J Livingston, Virginia P Sybert, Lynne T Smith, Beverly A Dale, Richard B Presland, K StephensAbstract:Epidermolysis bullosa simplex are dominant disorders of skin fragility characterized by intraepidermal blistering upon mild mechanical trauma. Skin fragility is caused by expression of either an abnormal Keratin 5 or an abnormal Keratin 14 protein, which compromises the structure and function of the Keratin cytoskeleton of basal cells. We report an epidermolysis bullosa simplex patient with a novel single base substitution (A→T1414) that changes the lysine residue at amino acid 472 to a non-sense codon (K472X). This change predicts the synthesis of a truncated Keratin 5, missing 119 amino acids, including the entire tail domain and the highly conserved KLLEGE motif at the carboxy terminus of the 2B domain of the central rod. Expression of an altered Keratin 5, of predicted mass and pI for the product of the K472X allele, was documented by one- and two-dimensional western blots of protein extracts from patient skin. Ultrastructural analysis of the patient's nonhyperkeratotic skin was remarkable for basal Keratinocytes with dense and irregular Keratin filaments proximal to the basement membrane. Keratinocytes, transfected with a cDNA carrying the A→T1414 non-sense mutation, overexpressed a truncated Keratin 5, and showed a disorganized and collapsed Keratin filament cytoskeleton. This is the second epidermolysis bullosa simplex patient reported with a premature termination mutation in the KLLEGE motif. The remarkable occurrence of severe palmar–plantar hyperkeratosis in both patients suggests that the Keratin 5 tail domain may have unrecognized, but important, normal functions in palmar–plantar tissues.
-
a common Keratin 5 gene mutation in epidermolysis bullosa simplex weber cockayne
Journal of Investigative Dermatology, 1995Co-Authors: Pamela Ehrlich, Virginia P Sybert, Anne Spencer, K StephensAbstract:The Weber-Cockayne subtype of epidermolysis bullosa simplex is an inherited skin-fragility disorder characterized by basal Keratinocyte lysis and epidermal blistering confined primarily to the hands and feet. The disorder results from a mutation in either the Keratin 5 or Keratin 14 gene, which encode the peptide components of the obligate heterodimeric Keratin intermediate filaments of the basal cell. We have determined that a T → G substitution mutation in Keratin 5, which results in a Ile → Ser change codon 161, is common among patients with the Weber-Cockayne disease variant, accounting for six of 13 cases tested. The observed high frequency of this mutation may result from either a mutational hot spot or a founder effect, The potential utility of this common mutation in confirming disease status in some at-risk individual is discussed.
-
A Common Keratin 5 Gene Mutation in Epidermolysis Bullosa Simplex–Weber-Cockayne
The Journal of investigative dermatology, 1995Co-Authors: Pamela Ehrlich, Virginia P Sybert, Anne Spencer, K StephensAbstract:The Weber-Cockayne subtype of epidermolysis bullosa simplex is an inherited skin-fragility disorder characterized by basal Keratinocyte lysis and epidermal blistering confined primarily to the hands and feet. The disorder results from a mutation in either the Keratin 5 or Keratin 14 gene, which encode the peptide components of the obligate heterodimeric Keratin intermediate filaments of the basal cell. We have determined that a T-->G substitution mutation in Keratin 5, which results in a Ile-->Ser change at codon 161, is common among patients with the Weber-Cockayne disease variant, accounting for six of 13 cases tested. The observed high frequency of this mutation may result from either a mutational hot spot or a founder effect. The potential utility of this common mutation in confirming disease status in some at-risk individual is discussed.
-
Epidermolysis bullosa simplex: a Keratin 5 mutation is a fully dominant allele in epidermal cytoskeleton function.
American journal of human genetics, 1995Co-Authors: K Stephens, Pamela Ehrlich, Robert J Livingston, Lynne T Smith, A Zlotogorski, Ellen M. Wijsman, Virginia P SybertAbstract:Abstract To explore the relationship between abnormal Keratin molecules, 10-nm intermediate filament (IF) organization, and epidermal fragility and blistering, we sought to determine the functional consequences of homozygosity for a dominant Keratin defect. We describe a family with an autosomal dominant skin-blistering disorder, epidermolysis bullosa simplex, Koebner subtype (EBS-K), that has a novel point mutation, occurring in the Keratin 5 gene (KRT5), that predicts the substitution of an evolutionarily conserved lysine by an asparagine residue (K173N). Unlike previous heterozygous mutations located within the initial segment of domain 1A of Keratin molecules, K173N heterozygosity did not result in severe disease or clumping of Keratin filaments. One family member was found to be homozygous for the K173N allele, having inherited it from each of her affected first-cousin parents. Despite a lack of normal Keratin 5 molecules, and an effective doubling of abnormal molecules, available for heterodimerization with Keratin 14 during IF formation, there were no significant differences in the clinical severity or the ultrastructural organization of the Keratin IF cytoskeleton of the homozygous individual. These data demonstrate that the K173N mutation behaves as a fully dominant allele and indicate that a limited number of abnormal Keratin molecules are sufficient to impair cytoskeletal function and elicit epidermal fragility and blistering.
Yuji Naito - One of the best experts on this subject based on the ideXlab platform.
-
Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-Keratin 5-specific transgenic mice.
Allergy, 2017Co-Authors: Mayumi Ueta, Junji Hamuro, Hiromi Nishigaki, Naomi Nakamura, Katsuhiko Shinomiya, Katsura Mizushima, Yuki Hitomi, Risa Tamagawa-mineoka, Norihiko Yokoi, Yuji NaitoAbstract:Background Our genome-wide association study documented an association between cold medicine related Stevens-Johnson syndrome / toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. Methods Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal Keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing Keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. Results We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was up-regulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly up-regulated in the epidermis of Ikzf1 Tg compared with wild-type. Conclusion Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation. This article is protected by copyright. All rights reserved.
-
Mucocutaneous inflammation in the Ikaros Family Zinc Finger 1-Keratin 5-specific transgenic mice.
Allergy, 2017Co-Authors: Mayumi Ueta, Junji Hamuro, Hiromi Nishigaki, Naomi Nakamura, Katsuhiko Shinomiya, Katsura Mizushima, Yuki Hitomi, Risa Tamagawa-mineoka, Norihiko Yokoi, Yuji NaitoAbstract:Our genomewide association study documented an association between cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis (CM-SJS/TEN) and Ikaros Family Zinc Finger 1 (IKZF1). Few studies examined biological and pathological functions of IKZF1 in mucosal immunity. We hypothesized that IKZF1 contributes to the mucocutaneous inflammation. Human skin and conjunctival tissues were obtained for immunohistological studies. Primary human conjunctival epithelial cells (PHCjECs) and adult human epidermal Keratinocytes (HEKa) also used for gene expression analysis. We also generated K5-Ikzf1-EGFP transgenic mice (Ikzf1 Tg) by introducing the Ik1 isoform into cells expressing Keratin 5, which is expressed in epithelial tissues such as the epidermis and conjunctiva, and then examined them histologically and investigated gene expression of the epidermis. Moreover, Ikzf1 Tg were induced allergic contact dermatitis. We found that human epidermis and conjunctival epithelium expressed IKZF1, and in PHCjECs and HEKa, the expression of IKZF1 mRNA was upregulated by stimulation with polyI:C, a TLR3 ligand. In Ikzf1 Tg, we observed dermatitis and mucosal inflammation including the ocular surface. In contact dermatitis model, inflammatory infiltrates in the skin of Ikzf1 Tg were significantly increased compared with wild type. Microarray analysis showed that Lcn2, Adh7, Epgn, Ifi202b, Cdo1, Gpr37, Duoxa1, Tnfrsf4, and Enpp5 genes were significantly upregulated in the epidermis of Ikzf1 Tg compared with wild type. Our findings support the hypothesis that Ikaros might participate in mucocutaneous inflammation. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
