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Indian Journal of Dermatology 2017Pachyonychia congenita (PC) is a rare autosomal dominant genetic skin disorder due to a mutation in any one of the five keratin genes, , , , , or . The main features are...
Pachyonychia congenita (PC) is a rare autosomal dominant genetic skin disorder due to a mutation in any one of the five keratin genes, , , , , or . The main features are palmoplantar keratoderma, plantar pain, and nail dystrophy. Cysts of various types, follicular hyperkeratosis, oral leukokeratosis, hyperhidrosis, and natal teeth may also be present. Four unrelated Indian families presented with a clinical diagnosis of PC. This was confirmed by genetic testing; mutations in were identified in all affected individuals.
PubMed: 28794556
DOI: 10.4103/ijd.IJD_321_16 -
Molecular Biology of the Cell May 2020Mitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS), and additional determinants...
Mitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS), and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes from null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5, null embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null for or exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences, and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics, and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders.
Topics: Animals; Cytoskeletal Proteins; Epidermis; Female; Keratin-16; Keratin-6; Keratinocytes; Keratins; Keratoderma, Palmoplantar; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mutation; Pachyonychia Congenita; Skin
PubMed: 32213122
DOI: 10.1091/mbc.E19-10-0565 -
The British Journal of Dermatology Aug 2014Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often...
BACKGROUND
Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17.
OBJECTIVES
To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years.
METHODS
Genomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced.
RESULTS
Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105.
CONCLUSIONS
By identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families.
Topics: Humans; Keratin-16; Keratin-17; Keratin-6; Keratins; Mutation; Pachyonychia Congenita; Pedigree
PubMed: 24611874
DOI: 10.1111/bjd.12958 -
Journal of the American Academy of... Nov 2022
Topics: Cross-Sectional Studies; Genetic Association Studies; Humans; Keratin-16; Keratin-6; Keratoderma, Palmoplantar; Mutation; Pachyonychia Congenita
PubMed: 35245567
DOI: 10.1016/j.jaad.2022.02.050 -
Clinical and Experimental Dermatology Jul 2019Mutations in keratin genes underlie a variety of epidermal and nonepidermal cell-fragility disorders, and are the genetic basis of many inherited palmoplantar...
Mutations in keratin genes underlie a variety of epidermal and nonepidermal cell-fragility disorders, and are the genetic basis of many inherited palmoplantar keratodermas (PPKs). Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1. Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former. We report four unrelated cases (one with sporadic EI and three with autosomal dominant PPK), due to two novel and two recurrent KRT1 mutations. Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern.
Topics: Adult; Family; Female; Humans; Hyperkeratosis, Epidermolytic; Keratin-1; Keratoderma, Palmoplantar; Male; Mutation; Young Adult
PubMed: 30288772
DOI: 10.1111/ced.13800 -
PLoS Genetics Jun 2019[This corrects the article DOI: 10.1371/journal.pgen.1007168.].
[This corrects the article DOI: 10.1371/journal.pgen.1007168.].
PubMed: 31233495
DOI: 10.1371/journal.pgen.1008230 -
Gaceta Medica de Mexico 2015Pachyonychia congenita is a group of autosomal dominant inheritance pattern disorders characterized by hypertrophic nail dystrophy There are two main clinical subtypes:...
Pachyonychia congenita is a group of autosomal dominant inheritance pattern disorders characterized by hypertrophic nail dystrophy There are two main clinical subtypes: type 1 and 2. Pachyonychia congenita type 2 is readily differentiated from type 1 by multiple steatocysts and/or presence of natal teeth and can be confirmed by mutations of KRT6B and KRT17. We report the case of a 33-year-o/d female patient with the missense mutation in KRT17 gene (c.280C> T, p.Arg94Cys) and discuss the several clinical features found with this mutation in the literature.
Topics: Adult; Female; Humans; Pachyonychia Congenita
PubMed: 25946540
DOI: No ID Found -
The British Journal of Dermatology Jan 2017
Topics: Aged; Female; Glucosyltransferases; Humans; Hyperpigmentation; Male; Middle Aged; Mutation, Missense; Pedigree; Skin Diseases, Genetic; Skin Diseases, Papulosquamous
PubMed: 27479915
DOI: 10.1111/bjd.14914 -
The Journal of Dermatology Dec 2017
Topics: Ectodermal Dysplasia; Humans; Keratin-6; Mutation; Pachyonychia Congenita; Polymorphism, Genetic
PubMed: 28815691
DOI: 10.1111/1346-8138.14001 -
The Journal of Investigative Dermatology Mar 2016The intermediate filament protein keratin 17 (Krt17) shows highly dynamic and inducible expression in skin physiology and pathology. Because Krt17 exerts physiologically...
The intermediate filament protein keratin 17 (Krt17) shows highly dynamic and inducible expression in skin physiology and pathology. Because Krt17 exerts physiologically important functions beyond providing structural stability to keratinocytes whereas abnormal Krt17 expression is a key feature of dermatoses such as psoriasis and pachyonychia congenita, the currently unclear regulation of Krt17 expression needs to be better understood. Using a rat model of radiation dermatitis, we report here that Krt17 expression initially is down-regulated but later is strongly up-regulated by ionizing radiation. The early down-regulation correlates with the activation of p53 signaling. Deletion of p53 abolishes the initial down-regulation but not its subsequent up-regulation, suggesting that p53 represses Krt17 transcription. Because previous work reported up-regulation of Krt17 by ultraviolet irradiation, which also activates p53 signaling, the effect of ultraviolet radiation was reexamined. This revealed that the initial down-regulation of Krt17 is conserved, but the up-regulation comes much faster. Chromatin immunoprecipitation analysis in vivo and electromobility shift assay in vitro identified two p53-binding sites in the promoter region of Krt17. Thus, p53 operates as a direct Krt17 repressor, which invites therapeutic targeting in dermatoses characterized by excessive Krt17 expression.
Topics: Animals; DNA Damage; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Immunohistochemistry; Keratins; Mice; Mice, Inbred C57BL; Polymerase Chain Reaction; Promoter Regions, Genetic; Protein Binding; Radiodermatitis; Random Allocation; Rats; Rats, Wistar; Sensitivity and Specificity; Tumor Suppressor Protein p53
PubMed: 26747697
DOI: 10.1016/j.jid.2015.12.021