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KERATIN 17-related recessive atypical pachyonychia congenita with variable hair and tooth anomalies.European Journal of Human Genetics :... Nov 2022We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two...
We present the first pachyonychia congenita (PC) to involve all ectodermal derivatives and the first recessive KRT17-related PC in total seven members of two consanguineous Pakistani families. This atypical PC is characterized by an unusual combination of pachyonychia, plantar keratoderma, folliculitis, alopecia, sparse eyebrows, dental anomalies and variable acanthosis nigricans of neck, dry skin, palmoplantar hyperhidrosis, recurrent blisters on soles and/or arms, rough sparse hair on scalp and keratosis pilaris. By exome sequencing we detected homozygous KRT17 c.281G>A (p.(Arg94His)) in affected individuals, and linkage mapping indicated a single locus. Heterozygous variants in KRT17 cause PC2 (PC-K17) with main characteristics of pachyonychia, subungual keratosis, palmoplantar keratoderma, hyperhidrosis, oral leukokeratosis and epidermal cysts, or steatocystoma multiplex, both with dominant inheritance. The causative variant has been reported in heterozygous state in a family afflicted with severe steatocystoma multiplex and in a sporadic PC2 case, and thus we also define a third phenotype related to the variant. Both exome sequencing and linkage mapping demonstrated recessive inheritance whereas Sanger sequencing indicated heterozygosity for the causal variant, reiterating caution for simple targeted sequencing for genetic testing. Testing parents for variants found in sibs could uncover recessive inheritance also in other KRT genes.
Topics: Humans; Eyebrows; Hyperhidrosis; Keratin-17; Mutation; Nails, Malformed; Pachyonychia Congenita; Steatocystoma Multiplex; Tooth Abnormalities; Pedigree
PubMed: 35676340
DOI: 10.1038/s41431-022-01128-4 -
Indian Journal of Dermatology,... 2023Background Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain...
Background Plantar keratoderma is a common finding in pachyonychia congenita, significantly impairing ambulation and quality of life. Due to the variation of pain reporting in pachyonychia congenita clinical studies, it is difficult to evaluate the efficacy of treatment outcomes for painful plantar keratodermas. Objectives To objectively analyse associations between plantar pain and activity levels in pachyonychia congenita patients using a wristband tracker. Methods Pachyonychia congenita patients and matched normal controls wore wristband activity trackers and completed a daily digital survey to record their highest and total pain scores (0-10 scale) each day for 28 consecutive days during four different seasons. Results Twenty four participants (12 pachyonychia congenita patients and 12 matched normal controls) completed the study. Pachyonychia congenita patients walked 1801.30 fewer steps/day (95% CI, -3666.4, 64.1) than normal controls (P = 0.072) and had greater average total [5.26; SD, 2.10] and highest (6.92; SD, 2.35) daily pain than normal controls [0.11 (SD, 0.47), 0.30 (SD, 0.22), respectively] (P < 0.001, both). On average, for each one unit increase in daily highest pain level, pachyonychia congenita activity decreased 71.54 steps/day (SE, 38.90, P = 0.066). Limitation The study had a small number of participants, limiting statistical power. Only pachyonychia congenita patients, ages 18 years or older, with keratin 6a, keratin 16, and keratin 17 mutations were included, limiting generalizability. Conclusion Pachyonychia congenita patients were less active with significantly higher pain than normal controls. There was an inverse correlation between pain and activity. Our findings suggest that wristband tracker technology may be used to evaluate treatment efficacy in future trials on severe plantar pain; therapeutic interventions that decrease plantar pain should correlate with significant increases in activity using wristband trackers.
Topics: Humans; Pachyonychia Congenita; Quality of Life; Fitness Trackers; Shoes; Keratin-6; Pain; Mutation; Walking
PubMed: 37317732
DOI: 10.25259/IJDVL_939_2022 -
Pharmaceutics Oct 2021Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold... (Review)
Review
Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.
PubMed: 34684016
DOI: 10.3390/pharmaceutics13101722 -
Indian Journal of Dermatology 2015Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by hyperkeratosis affecting the nails and palmoplantar areas, oral leucokeratosis,...
Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by hyperkeratosis affecting the nails and palmoplantar areas, oral leucokeratosis, and cystic lesions. It is classically subdivided into two major variants, PC-1 (Jadassohn-Lewandowski syndrome) and PC-2 (Jackson-Lawler syndrome), according to the localization of the mutations in the KRT6A/KRT16 or KRT6B/KRT17 genes, respectively. We report a 9-year-old male patient with a history of thickened, discolored nails, raised spiny skin lesions all over the body since birth with focal plantar keratoderma and absence of natal teeth.
PubMed: 26538744
DOI: 10.4103/0019-5154.159665 -
Advanced Drug Delivery Reviews Sep 2021Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the... (Review)
Review
Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease - recessive dystrophic epidermolysis bullosa (RDEB) - based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.
Topics: Animals; Epidermolysis Bullosa Dystrophica; Gene Transfer Techniques; Genetic Therapy; Humans; Polymers; Skin Diseases, Genetic; Translational Research, Biomedical
PubMed: 34293384
DOI: 10.1016/j.addr.2021.113842 -
The Journal of Clinical Investigation Jun 2016Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated...
Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16-/- mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16-/- mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16-/- footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCδ, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16-/- mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment.
Topics: Animals; Disease Models, Animal; Glutathione; Humans; Isothiocyanates; Keratin-16; Keratoderma, Palmoplantar; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Oxidative Stress; Pachyonychia Congenita; Phenotype; Phosphorylation; RNA, Messenger; Sulfoxides
PubMed: 27183391
DOI: 10.1172/JCI84870 -
JAAD Case Reports Nov 2022
PubMed: 36275875
DOI: 10.1016/j.jdcr.2022.09.011 -
Balkan Medical Journal Apr 2024
PubMed: 38619174
DOI: 10.4274/balkanmedj.galenos.2024.2024-2-23 -
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