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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 -
Clinical and Experimental Dermatology Jul 2021Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current...
BACKGROUND
Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants.
AIMS
We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity.
METHODS
We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ and Kruskal-Wallis tests.
RESULTS
We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation.
CONCLUSIONS
We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.
Topics: Age of Onset; Case-Control Studies; Child, Preschool; Cohort Studies; Genetic Variation; Heterozygote; Humans; Infant; Keratin-16; Keratin-17; Keratin-6; Keratins; Keratoderma, Palmoplantar; Keratosis; Leukoplakia, Oral; Mutation; Nail Diseases; Nails, Malformed; Pachyonychia Congenita; Phenotype; Predictive Value of Tests; Registries; Severity of Illness Index
PubMed: 33486795
DOI: 10.1111/ced.14569 -
The British Journal of Dermatology Mar 2020Epidermal differentiation is a multilevel process in which keratinocytes need to lose their organelles, including their mitochondria, by autophagy. Disturbed autophagy...
BACKGROUND
Epidermal differentiation is a multilevel process in which keratinocytes need to lose their organelles, including their mitochondria, by autophagy. Disturbed autophagy leads to thickening of the epidermis as seen in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17.
OBJECTIVES
To ask if mitophagy, the selective degradation of mitochondria by autophagy, is disturbed in PC and, if so, at which stage.
METHODS
Immortalized keratinocytes derived from patients with PC were used in fluorescence-based and biochemical assays to dissect the different steps of mitophagy.
RESULTS
PC keratinocytes accumulated old mitochondria and displayed disturbed clearance of mitochondria after mitochondrial uncoupling. However, early mitophagy steps and autophagosome formation were not affected. We observed that autolysosomes accumulate in PC and are not sufficiently recycled.
CONCLUSIONS
We propose an influence of keratins on autolysosomal degradation and recycling. What's already known about this topic? Terminal epidermal differentiation is a multistep process that includes the elimination of cellular components by autophagy. Autophagy-impaired keratinocytes have been shown to result in thickening of epidermal layers. Hyperkeratosis also occurs in pachyonychia congenita (PC), a rare skin disease caused by mutations in keratins 6, 16 and 17. What does this study add? Keratins contribute to mitochondrial quality control as well as maintenance of mitochondria-endoplasmic reticulum contact sites. Keratins influence autolysosomal maturation or reformation. What is the translational message? Overaged mitochondria and autolysosomes accumulate in PC. Mutations in keratin 6a lead to severely impaired mitophagy, which might contribute to PC pathogenesis.
Topics: Humans; Keratin-6; Keratins; Mitochondria; Mutation; Pachyonychia Congenita
PubMed: 31004504
DOI: 10.1111/bjd.18014 -
Therapy for dominant inherited diseases by allele-specific RNA interference: successes and pitfalls.Current Gene Therapy 2015RNA interference (RNAi) is a conserved mechanism for post-transcriptional gene silencing mediated by messenger RNA (mRNA) degradation. RNAi is commonly induced by... (Review)
Review
RNA interference (RNAi) is a conserved mechanism for post-transcriptional gene silencing mediated by messenger RNA (mRNA) degradation. RNAi is commonly induced by synthetic siRNA or shRNA which recognizes the targeted mRNA by base pairing and leads to target-mRNA degradation. RNAi may discriminate between two sequences only differing by one nucleotide conferring a high specificity of RNAi for its target mRNA. This property was used to develop a particular therapeutic strategy called "allele-specific-RNA interference" devoted to silence the mutated allele of genes causing dominant inherited diseases without affecting the normal allele. Therapeutic benefit was now demonstrated in cells from patients and animal models, and promising results of the first phase Ib clinical trial using siRNA-based allele-specific therapy were reported in Pachyonychia Congenita, an inherited skin disorder due to dominant mutations in the Keratin 6 gene. Our purpose is to review the successes of this strategy aiming to treat dominant inherited diseases and to highlight the pitfalls to avoid.
Topics: Alleles; Animals; Clinical Trials, Phase I as Topic; Gene Silencing; Genes, Dominant; Genetic Therapy; Humans; Mutation; Pachyonychia Congenita; RNA Interference; RNA, Messenger; RNA, Small Interfering
PubMed: 26264709
DOI: 10.2174/1566523215666150812115730 -
The British Journal of Dermatology Nov 2022
Topics: Humans; Pachyonychia Congenita; Hidradenitis Suppurativa; Keratins; Pedigree; Cytoskeletal Proteins; Keratin-6; Keratin-17; Keratin-16
PubMed: 35996837
DOI: 10.1111/bjd.21807 -
Case Reports in Dermatology 2015Pachyonychia congenita (PC) is a rare autosomal dominant disease whose main clinical features include hypertrophic onychodystrophy and palmoplantar keratoderma. The new...
BACKGROUND
Pachyonychia congenita (PC) is a rare autosomal dominant disease whose main clinical features include hypertrophic onychodystrophy and palmoplantar keratoderma. The new classification is based on genetic variants with mutations in keratin KRT6A, KRT6B, KRT6C, KRT16, KRT17, and an unknown mutation. Here, we present a case of PC with unusual clinical and histological features and a favorable response to oral acitretin.
CASE
A 49-year-old male presented with diffuse and striate palmoplantar keratoderma, thickened nails, knuckle pads, and pseudoainhum. Histology showed compact hyperkeratosis, prominent irregular acanthosis, and extensive epidermolytic hyperkeratosis, suggestive of Vörner's palmoplantar keratoderma. However, keratin 9 and 1 were not mutated, and full exome sequencing showed heterozygous missense mutation in type I keratin K16.
CONCLUSION
To our knowledge, epidermolytic hyperkeratosis has not been previously described with PC. Our patient had an excellent response, maintained over the last 5 years, to a low dose of acitretin. We wish to emphasize the crucial role of whole exome sequencing in establishing the correct diagnosis.
PubMed: 26464567
DOI: 10.1159/000438920 -
American Family Physician May 2020
Topics: Adult; Callosities; Diagnosis, Differential; Foot; Hand; Humans; Male; Pachyonychia Congenita
PubMed: 32412219
DOI: No ID Found -
Journal of the Peripheral Nervous... Dec 2018Nociceptin/orphanin FQ opioid peptide (NOP)-receptor (NOP-R) is a member of the opioid receptor family. NOP-R activation has demonstrated analgesic effects in...
Nociceptin/orphanin FQ opioid peptide (NOP)-receptor (NOP-R) is a member of the opioid receptor family. NOP-R activation has demonstrated analgesic effects in preclinical pain models without the addiction risks associated with other opiate targets. Pachyonychia congenita (PC) is a palmoplantar keratoderma characterized by neuropathic pain in affected skin. A cohort of KRT6A gene mutation PC patients with no other explanation for their neuropathic pain offered a unique opportunity to assess potential of NOP-R as a therapeutic target. Plantar biopsies from 10 PC patients and 10 age/gender matched controls were performed at the ball (PC-affected) and the arch (PC-unaffected) of the foot. NOP-R expression was assessed by immunohistochemistry. Localization of NOP-R in subsets of epidermal nerve fibers was investigated using the pan-neuronal marker PGP9.5, markers for unmyelinated peptidergic fibers (calcitonin gene-related peptide [CGRP] and substance P [SP]), as well as for myelinated Aδ and Aβ fibers (neurofilament H [NFH]). Robust NOP-R expression was detected in epidermal keratinocytes and in a subset of PGP9.5+ fibers in both epidermis and dermis, confirmed by western blot and absorption experiments with NOP-R peptide. NOP-R expression in keratinocytes was significantly reduced in PC-affected plantar skin compared with PC-unaffected skin. In addition, NOP-R expression occurred in dermal NFH+ myelinated fibers in all groups, although few CGRP+ fibers co-expressed NOP-R. Furthermore, most SP+ fibers also co-expressed NOP-R. These findings indicate that NOP-R is expressed on epidermal keratinocytes, as well as on epidermal and dermal nerve fibers and has potential as a promising target to treat neuropathic pain in PC.
Topics: Adult; Aged; Dermis; Epidermis; Female; Foot; Humans; Keratin-6; Keratinocytes; Male; Middle Aged; Nerve Fibers; Neuralgia; Pachyonychia Congenita; Receptors, Opioid; Young Adult; Nociceptin Receptor
PubMed: 30255608
DOI: 10.1111/jns.12288 -
The Journal of Investigative Dermatology May 2018Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita is caused by mutations in keratin genes and...
Sex is an influential factor regarding pathophysiology and therapeutic response in human disease. Pachyonychia congenita is caused by mutations in keratin genes and typified by dystrophic lesions affecting nails, glands, oral mucosa, and palmar-plantar epidermis. Painful palmar-plantar keratoderma (PPK) severely impairs mobility in pachyonychia congenita. Mice genetically null for keratin 16 (Krt16), one of the genes mutated in pachyonychia congenita, develop pachyonychia congenita-like PPK. In male Krt16 mice, oxidative stress associated with impaired glutathione synthesis and nuclear factor erythroid-derived 2 related factor 2 (NRF2)-dependent gene expression precedes PPK onset, which can be prevented by topical sulforaphane-mediated activation of NRF2. We report here that sulforaphane treatment fails to activate NRF2 and prevent PPK in female Krt16 mice despite a similar set of molecular circumstances. Follow-up studies reveal a temporal shift in PPK onset in Krt16 females, coinciding with sex-specific fluctuations in footpad skin glutathione levels. Dual treatment with sulforaphane and diarylpropionitrile, an estrogen receptor beta selective agonist, results in NRF2 activation, normalization of glutathione levels, and prevention of PPK in female Krt16 mice. These findings point to a sex difference in NRF2 responsiveness that needs be considered when exploring NRF2 as a therapeutic target in skin disorders.
Topics: Animals; Disease Models, Animal; Estrogen Receptor alpha; Female; Glutathione; Humans; Isothiocyanates; Keratin-16; Keratoderma, Palmoplantar; Male; Mice; NF-E2-Related Factor 2; Nitriles; Pachyonychia Congenita; Propionates; Sex Characteristics; Sulfoxides
PubMed: 29277538
DOI: 10.1016/j.jid.2017.09.054 -
Indian Dermatology Online Journal 2016Pachyonychia congenita is a rare type of ectodermal dysplasia further classified into 4 types. Cutaneous manifestations seen in most of the cases of Pachyonychia...
Pachyonychia congenita is a rare type of ectodermal dysplasia further classified into 4 types. Cutaneous manifestations seen in most of the cases of Pachyonychia congenita include palmoplantar keratoderma, follicular hyperkeratosis, wedge shaped nails, oral leukokeratosis and woolly hair. A 25-year-old male presented to us with thickened nails and scanty scalp hair. On examination, we noticed hyperkeratotic plaques over both the soles, palmoplantar hyperhidrosis and yellowish discoloration, wedging with subungual hyperkeratosis of all the nails. Follicular hyperkeratotic papules and steatocystoma multiplex were also observed over the scalp and face. The patient had history of natal teeth and on dental examination, lower central incisors were absent. All cutaneous changes in our case had manifested first in the 2(nd) decade except for natal teeth. All the above features suggested the diagnosis of pachyonychia congenita with late onset (PC tarda), which is an infrequently reported rare variant.
PubMed: 27559502
DOI: 10.4103/2229-5178.185463