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Indian Journal of Dermatology 2016
PubMed: 27904190
DOI: 10.4103/0019-5154.193686 -
JAAD Case Reports Nov 2022
PubMed: 36275875
DOI: 10.1016/j.jdcr.2022.09.011 -
Journal of Dermatological Science Sep 2008The field of science and medicine has experienced a flood of data and technology associated with the human genome project. Over 10,000 human diseases have been... (Review)
Review
The field of science and medicine has experienced a flood of data and technology associated with the human genome project. Over 10,000 human diseases have been genetically defined, but little progress has been made with respect to the clinical application of this knowledge. A notable exception to this exists for pachyonychia congenita (PC), a rare, dominant-negative keratin disorder. The establishment of a non-profit organization, PC Project, has led to an unprecedented coalescence of patients, scientists, and physicians with a unified vision of developing novel therapeutics for PC. Utilizing the technological by-products of the human genome project, such as RNA interference (RNAi) and quantitative RT-PCR (qRT-PCR), physicians and scientists have collaborated to create a candidate siRNA therapeutic that selectively inhibits a mutant allele of KRT6A, the most commonly affected PC keratin. In vitro investigation of this siRNA demonstrates potent inhibition of the mutant allele and reversal of the cellular aggregation phenotype. In parallel, an allele-specific quantitative real-time RT-PCR assay has been developed and validated on patient callus samples in preparation for clinical trials. If clinical efficacy is ultimately demonstrated, this "first-in-skin" siRNA may herald a paradigm shift in the treatment of dominant-negative genetic disorders.
Topics: Animals; Clinical Trials as Topic; Disease Models, Animal; Genetic Therapy; Humans; Keratin-6; Models, Genetic; Pachyonychia Congenita; Point Mutation; RNA, Small Interfering; Skin Diseases, Genetic
PubMed: 18495438
DOI: 10.1016/j.jdermsci.2008.04.003 -
PLoS Genetics Jan 2018Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A,...
Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita.
Topics: Adult; Amino Acid Substitution; Animals; Cells, Cultured; Child; Dental Caries; Dental Enamel; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Keratin-6; Keratins; Male; Mice; Middle Aged; Pachyonychia Congenita; Polymorphism, Single Nucleotide; Rats; Tooth Erosion
PubMed: 29357356
DOI: 10.1371/journal.pgen.1007168 -
Journal of Dermatological Science Mar 2015Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful...
BACKGROUND
Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear.
OBJECTIVE
To better understand PC pathogenesis.
METHODS
RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples.
RESULTS
A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis.
CONCLUSION
Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics.
Topics: Down-Regulation; Enzymes; Gene Expression Profiling; Humans; Keratin-16; Keratin-17; Keratin-6; Keratins; Oligonucleotide Array Sequence Analysis; Pachyonychia Congenita; Pain; RNA, Messenger; Transcriptome; Up-Regulation
PubMed: 25656049
DOI: 10.1016/j.jdermsci.2015.01.001 -
The Journal of Investigative Dermatology Dec 2001Thirteen patients with pachyonychia congenita types 1 and 2 were studied, two of which had a family history of pachyonychia and 11 of which were sporadic cases....
Thirteen patients with pachyonychia congenita types 1 and 2 were studied, two of which had a family history of pachyonychia and 11 of which were sporadic cases. Heterozygous mis-sense or small in-frame insertion/deletion mutations were detected in the genes encoding keratins K6a, K16, and K17 in all cases. Three novel mutations, F174V, E472K, and L469R were found in the K6a gene. Two novel mutations, M121T and L128Q were detected in K16. Similarly, three novel mutations, L95P, S97del, and L99P were found in K17. In addition, we identified recurrent mutations N171del (three instances) and F174S in K6a and R94H in K17. Analysis of both phenotype and genotype data led to the following conclusions: (i) K6a or K16 mutations produce the pachyonychia congenita type 1 phenotype, whereas K17 (or K6b) mutations cause pachyonychia congenita type 2; (ii) the presence of pilosebaceous cysts following puberty is the best indicator of pachyonychia congenita type 2; (iii) prepubescent patients are more difficult to classify due to the lack of cysts; and (iv) natal teeth are indicative of pachyonychia congenita type 2, although their absence does not preclude the pachyonychia congenita type 2 phenotype. This study establishes useful diagnostic criteria for pachyonychia congenita types 1 and 2, which will help limit unnecessary DNA analysis in the diagnosis and management of this genetically heterogeneous group of genodermatoses.
Topics: DNA Mutational Analysis; DNA Primers; Ectodermal Dysplasia; Gene Deletion; Genotype; Humans; Keratins; Keratoderma, Palmoplantar; Mutation, Missense; Nail Diseases; Phenotype; Restriction Mapping
PubMed: 11886499
DOI: 10.1046/j.0022-202x.2001.01565.x -
The Journal of Investigative Dermatology Jul 2012In this issue, Wilson et al. report the first case of homozygous dominant negative mutations in KRT17 in pachyonychia congenita (PC). Homozygous dominant negative...
In this issue, Wilson et al. report the first case of homozygous dominant negative mutations in KRT17 in pachyonychia congenita (PC). Homozygous dominant negative mutations are a rare occurrence in keratin disorders and this is a first report in PC. These mutations cause a distinct sub-phenotype of PC that is more severe in the offspring of affected parents and has associated alopecia.
Topics: Alopecia; Female; Humans; Keratin-17; Male; Mutation, Missense; Pachyonychia Congenita
PubMed: 22695286
DOI: 10.1038/jid.2012.121 -
The Journal of Investigative Dermatology Jun 2000The hard-keratin-containing portion of the murine hair shaft displays a positive immunoreactivity with an antibody against the soft epithelial keratin, K17. The...
The hard-keratin-containing portion of the murine hair shaft displays a positive immunoreactivity with an antibody against the soft epithelial keratin, K17. The K17-expressing cell population is located in the medulla compartment of the hair. Consistent with this observation, K17-containing cells also occur in the presumptive medulla precursor cells located in the hair follicle matrix. Western blot analysis of hair extracts prepared from a number of mouse strains confirms this observation and suggests that K17 expression in the hair shaft is a general trait in this species. The expression of K17 in human hair extracts is restricted to eyebrow and facial hair samples. These are the major sites for the occurrence of the pili torti (twisted hair) phenotype in the type 2 (Jackson-Lawler) form of pachyonychia congenita, previously shown to arise from inherited K17 mutations. Given that all forms of pachyonychia congenita show an involvement of the nail, we compared the expression of the two other genes mutated in pachyonychia congenita diseases, K6 and K16, with that of K17 in human nail. All three keratins are abundantly expressed within the nail bed epithelium, whereas K17 protein is expressed in the nail matrix, which contains the epithelial cell precursors for the nail plate. Our data suggest a role for K17 in the formation and maintenance of various skin appendages and directly support the concept that pachyonychia congenita is a disease of the nail bed.
Topics: Animals; Cats; Dogs; Ectodermal Dysplasia; Eyebrows; Face; Green Fluorescent Proteins; Hair; Haplorhini; Humans; Indicators and Reagents; Keratins; Luminescent Proteins; Mice; Nails; Phenotype; Rats; Swine
PubMed: 10844551
DOI: 10.1046/j.1523-1747.2000.00986.x -
American Family Physician May 2020
Topics: Adult; Callosities; Diagnosis, Differential; Foot; Hand; Humans; Male; Pachyonychia Congenita
PubMed: 32412219
DOI: No ID Found -
The Journal of Investigative... Oct 2005Dominant mutations that interfere with the assembly of keratin filaments cause painful and disfiguring epidermal diseases like pachyonychia congenita and epidermolysis... (Review)
Review
Dominant mutations that interfere with the assembly of keratin filaments cause painful and disfiguring epidermal diseases like pachyonychia congenita and epidermolysis bullosa simplex. Genetic therapies for such diseases must either suppress the production of the toxic proteins or correct the genetic defect in the chromosome. Because epidermal skin cells may be genetically modified in tissue culture or in situ, gene correction is a legitimate goal for keratin diseases. In addition, recent innovations, such as RNA interference in animals, make an RNA knockdown approach plausible in the near future. Although agents of RNA reduction (small interfering RNA, ribozymes, triplex oligonucleotides, or antisense DNA) can be delivered as nucleotides, the impermeability of the skin to large charged molecules presents a serious impediment. Using viral vectors to deliver genes for selective inhibitors of gene expression presents an attractive alternative for long-term treatment of genetic disease in the skin.
Topics: Animals; Darier Disease; Dependovirus; Ectodermal Dysplasia; Epidermolysis Bullosa Simplex; Gene Silencing; Gene Targeting; Genes, Dominant; Genetic Therapy; Genetic Vectors; Humans; Keratins; Keratoderma, Palmoplantar; Mice; Mutation; Nails, Malformed; Oligonucleotides, Antisense; RNA Interference; RNA, Catalytic; RNA, Small Interfering
PubMed: 16250209
DOI: 10.1111/j.1087-0024.2005.10207.x