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The Journal of Investigative Dermatology May 2018Pachyonychia congenita is an incurable and often debilitating genodermatosis. Topical application of the antioxidative response inducer sulforaphane, however, alleviates...
Pachyonychia congenita is an incurable and often debilitating genodermatosis. Topical application of the antioxidative response inducer sulforaphane, however, alleviates disease symptoms in a murine pachyonychia congenita model, forecasting clinical benefits. The Coulombe laboratory now reports sex-dependent differences in sulforaphane responsiveness of pachyonychia congenita mice, thereby dampening treatment expectations but also unveiling novel aspects of sex-specific oxidative stress reactivity in the epidermis.
Topics: Animals; Epidermis; Female; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress; Pachyonychia Congenita; Sex Characteristics
PubMed: 29681388
DOI: 10.1016/j.jid.2017.12.017 -
The Journal of Investigative Dermatology May 2011Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC...
Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC Research Registry is a database with information on patients' symptoms as well as genotypes. We sought to describe the heterogeneity of clinical symptoms and to investigate possible genotype-phenotype correlations in patients with two types of K16 mutations, p.Asn125 and p.Arg127, causing the PC-16 subtype of PC. We found that clinical symptoms depended on the type of amino-acid substitution. Patients with p.Asn125Asp and p.Arg127Pro mutations exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. We speculate that amino-acid substitutions causing larger, more disruptive changes to the K16 protein structure, such as a change in amino-acid charge in the p.Asn125Asp mutation or a bulky proline substitution in the p.Arg127Pro mutation, may also lead to more severe disease phenotypes. The variation in phenotypes seen with different substitutions at the same mutation site suggests a genotype-phenotype correlation. Knowledge of the exact gene defect is likely to assist in predicting disease prognosis and clinical management.
Topics: Child; Child, Preschool; Female; Genetic Association Studies; Humans; Keratin-16; Keratoderma, Palmoplantar; Male; Mutation; Pachyonychia Congenita; Quality of Life; Severity of Illness Index
PubMed: 21160496
DOI: 10.1038/jid.2010.373 -
Human Molecular Genetics Jul 2019The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is...
The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is robustly induced when the epidermis experiences chemical, mechanical or environmental stress. Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin. Krt16-null mice develop footpad lesions that mimic PC-associated PPK, providing an opportunity to decipher its pathophysiology, and develop therapies. We report on insight gained from a genome-wide analysis of gene expression in PPK-like lesions of Krt16-null mice. Comparison of this data set with publicly available microarray data of PPK lesions from individuals with PC revealed significant synergies in gene expression profiles. Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation. Effective prevention of PPK-like lesions in Krt16-null paw skin (via topical delivery of the Nrf2 inducer sulforaphane) involves the stimulation of Krt9 expression. These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy. Further, we report on the novel observation that keratin 16 can localize to the nucleus of epithelial cells, implying a potential nuclear function that may be relevant to PC and FNEPPK.
Topics: Animals; Cell Differentiation; Dermis; HeLa Cells; Humans; Interleukin-1; Isothiocyanates; Kelch-Like ECH-Associated Protein 1; Keratin-16; Keratin-9; Keratinocytes; Keratins; Keratoderma, Palmoplantar; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Mutation, Missense; NF-E2-Related Factor 2; Signal Transduction; Sulfoxides; Tissue Array Analysis
PubMed: 31220272
DOI: 10.1093/hmg/ddz050 -
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 -
The Journal of Investigative Dermatology May 2011Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the...
Molecular characterization and assessment of therapeutic outcomes for inherited cutaneous disorders requires faithful preclinical models. In this study we report the establishment of two different skin-humanized pachyonychia congenita (PC) model systems, based on permanent engraftment of bioengineered skin equivalents generated from patient skin cells onto immunodeficient mice. Using keratinocytes and fibroblasts isolated from unaffected skin biopsies of two PC patients carrying the p.Asn171Lys mutation of the keratin 6a gene (KRT6A), we were able to regenerate PC-derived human skin that appeared phenotypically normal, but developed sustained PC features after the use of an acute hyperproliferative stimulus (i.e., tape stripping). In contrast, the use of keratinocytes from an affected area (i.e., plantar callus) from a different patient carrying the KRT6A mutation p.Asn171Asp led to a full recapitulation of the phenotype that included marked acanthosis and epidermal blistering after minor trauma. The ability to generate large numbers of PC skin-engrafted mice will enable the testing of novel pharmacological or gene-based therapies for this as yet untreatable disease.
Topics: Animals; Blister; Disease Models, Animal; Female; Fibroblasts; Humans; Keratin-6; Keratinocytes; Mice; Mice, Nude; Mutation; Pachyonychia Congenita; Skin
PubMed: 21150925
DOI: 10.1038/jid.2010.353 -
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 -
Dermatology Online Journal Oct 2003A 5-year-old girl presented with extensor hyperkeratotic papules and subungual hyperkeratosis with nail-plate discoloration affecting all twenty nails. The mother...
A 5-year-old girl presented with extensor hyperkeratotic papules and subungual hyperkeratosis with nail-plate discoloration affecting all twenty nails. The mother reported that her daughter had natal teeth. By report, the father has a similar history and constellation of clinical findings. The patient's clinical presentation and history was consistent with pachyonychia congenita, which is a genodermatosis linked to mutations in the genes encoding keratins 6, 16, and 17.
Topics: Child, Preschool; Female; Genes, Dominant; Humans; Keratins; Keratosis; Mutation; Nail Diseases
PubMed: 14594585
DOI: No ID Found -
The American Journal of Pathology Sep 2008Keratins 6a and b (K6a, K6b) belong to a subset of keratin genes with constitutive expression in epithelial appendages, and inducible expression in additional epithelia,...
Keratins 6a and b (K6a, K6b) belong to a subset of keratin genes with constitutive expression in epithelial appendages, and inducible expression in additional epithelia, when subjected to environmental challenges or disease. Mutations in K6a or K6b cause a broad spectrum of epithelial lesions that differentially affect nail, hair, and glands in humans. Some lesions reflect a loss of the structural support function shared by K6, other keratins, and intermediate filament proteins. The formation of sebaceous gland-derived epithelial cysts does not fit this paradigm, raising the question of the unique functions of different K6 isoforms in this setting. Here, we exploit a mouse model of constitutively expressed Gli2, a Hedgehog (Hh) signal effector, to show that K6a expression correlates with duct fate in sebaceous glands (SGs). Whether in the setting of Gli2 transgenic mice skin, which develops a prominent SG duct and additional pairs of highly branched SGs, or in wild-type mouse skin, K6a expression consistently coincides with Hh signaling in ductal tissue. Gli2 expression modestly transactivates a K6a promoter-driven reporter in heterologous systems. Our findings thus identify K6 as a marker of duct fate in SGs, partly in response to Hh signaling, with implications for the pathological expansion of SGs that arises in the context of certain keratin-based diseases and related disorders.
Topics: Animals; Fluorescent Antibody Technique; Gene Expression; Hedgehog Proteins; Humans; Immunohistochemistry; In Situ Hybridization; Keratin-6; Kruppel-Like Transcription Factors; Male; Mice; Mice, Transgenic; Pachyonychia Congenita; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Sebaceous Glands; Signal Transduction; Transfection; Zinc Finger Protein Gli2
PubMed: 18688029
DOI: 10.2353/ajpath.2008.071089 -
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