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Proceedings of the National Academy of... Nov 2013Mutations in the type I keratin 16 (Krt16) and its partner type II keratin 6 (Krt6a, Krt6b) cause pachyonychia congenita (PC), a disorder typified by dystrophic nails,...
Mutations in the type I keratin 16 (Krt16) and its partner type II keratin 6 (Krt6a, Krt6b) cause pachyonychia congenita (PC), a disorder typified by dystrophic nails, painful hyperkeratotic calluses in glabrous skin, and lesions involving other epithelial appendages. The pathophysiology of these symptoms and its relationship to settings in which Krt16 and Krt6 are induced in response to epidermal barrier stress are poorly understood. We report that hyperkeratotic calluses arising in the glabrous skin of individuals with PC and Krt16 null mice share a gene expression signature enriched in genes involved in inflammation and innate immunity, in particular damage-associated molecular patterns. Transcriptional hyper-activation of damage-associated molecular pattern genes occurs following de novo chemical or mechanical irritation to ear skin and in spontaneously arising skin lesions in Krt16 null mice. Genome-wide expression analysis of normal mouse tail skin and benign proliferative lesions reveals a tight, context-dependent coregulation of Krt16 and Krt6 with genes involved in skin barrier maintenance and innate immunity. Our results uncover a role for Krt16 in regulating epithelial inflammation that is relevant to genodermatoses, psoriasis, and cancer and suggest a avenue for the therapeutic management of PC and related disorders.
Topics: Animals; Blotting, Western; DNA Primers; Gene Expression Profiling; Gene Regulatory Networks; Humans; Immunity, Innate; Keratin-16; Keratin-6; Mice; Microarray Analysis; Microscopy, Electron, Transmission; Pachyonychia Congenita; Real-Time Polymerase Chain Reaction
PubMed: 24218583
DOI: 10.1073/pnas.1309576110 -
The Journal of Investigative Dermatology May 2011RNA interference (RNAi) is an evolutionarily conserved mechanism that results in specific gene inhibition at the mRNA level. The discovery that short interfering RNAs...
RNA interference (RNAi) is an evolutionarily conserved mechanism that results in specific gene inhibition at the mRNA level. The discovery that short interfering RNAs (siRNAs) are selective, potent, and can largely avoid immune surveillance has resulted in keen interest to develop these inhibitors as therapeutics. A single nucleotide-specific siRNA (K6a_513a.12, also known as TD101) was recently evaluated in a phase 1b clinical trial for the rare skin disorder, pachyonychia congenita (PC). To develop a clinical trial molecular end point for this type of trial, methods were developed to: (1) isolate total RNA containing amplifiable mRNA from human skin and callus material; (2) quantitatively distinguish the single-nucleotide mutant mRNA from wild-type K6a mRNA in both patient-derived keratinocytes and patient callus; and (3) demonstrate that repeated siRNA treatment results in sustained inhibition of mutant K6a mRNA in patient-derived keratinocyte cultures. These methods allow noninvasive sampling and monitoring of gene expression from patient-collected shavings and may be useful in evaluating the effectiveness of RNAi-based therapeutics, including inhibitors that specifically target single-nucleotide mutations.
Topics: Bony Callus; Cells, Cultured; Clinical Trials as Topic; Humans; Keratin-6; Keratinocytes; Pachyonychia Congenita; Polymorphism, Single Nucleotide; RNA Interference; RNA, Messenger; RNA, Small Interfering; Skin
PubMed: 21191405
DOI: 10.1038/jid.2010.372 -
Indian Journal of Dermatology,... 2012Nails are cutaneous appendages mostly involved in mechanical functions. However, nails may reflect presence of various systemic disorders evidenced by alteration of... (Review)
Review
Nails are cutaneous appendages mostly involved in mechanical functions. However, nails may reflect presence of various systemic disorders evidenced by alteration of their shape, size, color or texture. Genodermatoses are multisystem disorders with cutaneous involvement. Many of the genodermatoses present with nail changes and some of these may be the clinical pointers to the diagnosis. Diagnostic clues to various genodermatoses derived from nail findings have been discussed.
Topics: Humans; Nail-Patella Syndrome; Pachyonychia Congenita; Skin Diseases; Yellow Nail Syndrome
PubMed: 22565426
DOI: 10.4103/0378-6323.95441 -
The Journal of Investigative Dermatology Jan 2008Pachyonychia congenita (PC) is an autosomal-dominant keratin disorder where the most painful, debilitating aspect is plantar keratoderma. PC is caused by mutations in...
Pachyonychia congenita (PC) is an autosomal-dominant keratin disorder where the most painful, debilitating aspect is plantar keratoderma. PC is caused by mutations in one of four keratin genes; however, most patients carry K6a mutations. Knockout mouse studies suggest that ablation of one of the several K6 genes can be tolerated owing to compensatory expression of the others. Here, we have developed potent RNA interference against K6a as a paradigm for treating a localized dominant skin disorder. Four small interfering RNAs (siRNAs) were designed against unique sequences in the K6a 3'-untranslated region. We demonstrated near-complete ablation of endogenous K6a protein expression in two keratinocyte cell lines, HaCaT and NEB-1, by transient transfection of each of the four K6a siRNAs. The siRNAs were effective at very low, picomolar concentrations. One potent lead K6a inhibitor, which was highly specific for K6a, was tested in a mouse model where reporter gene constructs were injected intradermally into mouse paw and luciferase activity was used as an in vivo readout. Imaging in live mice using the Xenogen IVIS system demonstrated that the K6a-specific siRNA strongly inhibited bicistronic K6a-luciferase gene expression in vivo. These data suggest that siRNAs can specifically and very potently target mutated genes in the skin and support development of these inhibitors as potential therapeutics.
Topics: 3' Untranslated Regions; Animals; Cell Line; Female; Humans; Keratin-6; Keratinocytes; Mice; Pachyonychia Congenita; RNA, Small Interfering
PubMed: 17762855
DOI: 10.1038/sj.jid.5701040 -
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 -
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 -
Molecular Therapy : the Journal of the... Feb 2010The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is... (Randomized Controlled Trial)
Randomized Controlled Trial
The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is currently available. We have completed a phase Ib clinical trial for treatment of PC utilizing the first short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA. The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial. Randomly assigned solutions of TD101 or vehicle control were injected in symmetric plantar calluses on opposite feet. No adverse events occurred during the trial or in the 3-month washout period. Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot. This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patient's siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.
Topics: Adult; Female; Humans; Mutation; Pachyonychia Congenita; RNA, Small Interfering; Skin Diseases
PubMed: 19935778
DOI: 10.1038/mt.2009.273 -
Dermatology Online Journal Jan 2007A 3-year-old girl presented with subungual hyperkeratosis and nail plates with increased transverse curvature, distal elevation, yellow-brown discoloration, and mild...
A 3-year-old girl presented with subungual hyperkeratosis and nail plates with increased transverse curvature, distal elevation, yellow-brown discoloration, and mild thickening. The changes, which affected all 20 nails, had developed during the first year of life. Mucocutaneous examination showed the presence of median rhomboid glossitis. The patient's mother had similar nail changes, which had been present since infancy as well as a focal plantar keratoderma and hyperhidrosis. The patient's clinical presentation and history were compatible with a diagnosis of pachyonychia congenita, a rare heritable disease that affects the nails, skin, oral and laryngeal mucosae, teeth, and hair. Dominant-negative mutations in four keratin genes (K6a, K6b, K16, and K17) lead to keratinocyte fragility and the resultant pachyonychia congenita phenotype. Successful targeted therapies are currently lacking for this oftentimes disabling disorder. Although oral manifestations are a common feature of PC, to our knowledge, this represents the first report of median rhomboid glossitis in association with PC.
Topics: Child, Preschool; Diagnosis, Differential; Female; Genes, Dominant; Genetic Predisposition to Disease; Glossitis; Humans; Keratin-16; Keratin-17; Keratin-6; Mutation; Pachyonychia Congenita
PubMed: 17511954
DOI: No ID Found -
The Journal of Investigative Dermatology Feb 2010The palmoplantar keratodermas (PPKs) are a large group of clinically and genetically heterogeneous genodermatoses. The gene defects underlying many PPKs still need to be...
The palmoplantar keratodermas (PPKs) are a large group of clinically and genetically heterogeneous genodermatoses. The gene defects underlying many PPKs still need to be resolved to facilitate definitive molecular diagnosis and genetic counseling. Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16, or KRT17, cause pachyonychia congenita (PC), characterized by hypertrophic nail dystrophy and other ectodermal features. In PC, focal PPK (FPPK) is the most painful and debilitating phenotypic feature. Some families presenting with FPPK alone, or with minimal nail changes, carry mutations in KRT16; however, most FPPK families do not harbor mutations in any of these keratin genes. Here, we report three unrelated families who presented with familial FPPK with minor or absent nail changes. The four PC/FPPK-related keratin genes were excluded; however, mutational analysis of the recently identified KRT6C gene, encoding keratin K6c, showed heterozygous in-frame deletion mutations in all three kindreds. Affected members of Families 1 and 2 carried the same mutation, p.Asn172del. In Family 3, the mutation p.Ile462-Glu470del co-segregated with the disease. KRT6C was shown to be expressed in the plantar epidermis using reverse transcription-PCR, consistent with the phenotype observed in this tissue. These data expand the genetic testing repertoire for the PPKs.
Topics: DNA Mutational Analysis; Female; Gene Deletion; Genes, Dominant; Genetic Linkage; Heterozygote; Humans; Keratin-6; Keratins; Keratoderma, Palmoplantar; Male; Mutation; Pedigree; Phenotype; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 19609311
DOI: 10.1038/jid.2009.215