Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 115
Filter
Add more filters

Country/Region as subject
Publication year range
1.
Am J Hum Genet ; 111(5): 896-912, 2024 05 02.
Article in English | MEDLINE | ID: mdl-38653249

ABSTRACT

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.


Subject(s)
DNA Methylation , Epigenesis, Genetic , Keratinocytes , Mosaicism , Porokeratosis , Promoter Regions, Genetic , Porokeratosis/genetics , Porokeratosis/pathology , Humans , Keratinocytes/metabolism , Keratinocytes/pathology , Promoter Regions, Genetic/genetics , Male , Alleles , Female
2.
Nat Immunol ; 13(8): 744-52, 2012 Jun 24.
Article in English | MEDLINE | ID: mdl-22729248

ABSTRACT

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.


Subject(s)
Chemokines/biosynthesis , Hair Follicle/immunology , Langerhans Cells/physiology , Stress, Physiological , Alopecia , Animals , Cell Movement , Chemokine CCL20/biosynthesis , Chemokine CCL8/biosynthesis , Chemokines/metabolism , Hair Follicle/metabolism , Humans , Keratinocytes/metabolism , Langerhans Cells/immunology , Mice , Mice, Hairless , Receptors, CCR2/metabolism , Receptors, CCR6/metabolism , Receptors, CCR8/metabolism , Skin/immunology
3.
Exp Dermatol ; 33(4): e15072, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38576105

ABSTRACT

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).


Subject(s)
Ichthyosiform Erythroderma, Congenital , Ichthyosis, Lamellar , Ichthyosis , Humans , Ichthyosis, Lamellar/genetics , Ichthyosis, Lamellar/pathology , DNA, Complementary , Genes, Recessive , Mutation , Ichthyosis/genetics , Ichthyosiform Erythroderma, Congenital/genetics , Genetic Association Studies , ATP-Binding Cassette Transporters/genetics
4.
J Med Genet ; 59(9): 865-877, 2022 Sep.
Article in English | MEDLINE | ID: mdl-34815299

ABSTRACT

BACKGROUND: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated. METHODS: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations. RESULTS: Sixty-six patients in 48 families (33 males/females; 0-59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype-phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE. CONCLUSION: This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.


Subject(s)
Abnormalities, Multiple , Ehlers-Danlos Syndrome , Abnormalities, Multiple/genetics , Ehlers-Danlos Syndrome/diagnosis , Ehlers-Danlos Syndrome/genetics , Female , Genetic Association Studies , Humans , Male , Phenotype , Sulfotransferases/genetics
5.
J Hum Genet ; 67(11): 675-678, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35970985

ABSTRACT

Pierre-Robin sequence (PRS) is a rare, congenital defect presenting with micrognathia, glossoptosis, and airway obstruction with variable inclusion of a cleft palate. Overlapping PRS with neurofibromatosis type 2 (NF2) is a syndrome caused by a chromosome 22q12 microdeletion including NF2. We describe a patient with severe early-onset NF2 overlapping with PRS that showed micrognathia, glossoptosis, and a mild form of cleft palate. We detected a de novo chromosome 22q12 microdeletion including MN1 and NF2 in the patient. Previous cases of overlapping PRS and NF2 caused by the chromosome 22q12 microdeletions showed severe NF2 phenotypes with variable severity of cleft palate and microdeletions of varying sizes. Genotype-phenotype correlations and comparison of the size and breakpoint of microdeletions suggest that some modifier genes distal to MN1 and NF2 might be linked to the cleft palate severity.


Subject(s)
Cleft Palate , Glossoptosis , Micrognathism , Neurofibromatosis 2 , Pierre Robin Syndrome , Humans , Pierre Robin Syndrome/genetics , Neurofibromatosis 2/genetics , Cleft Palate/genetics , Micrognathism/genetics , Chromosomes , Trans-Activators/genetics , Tumor Suppressor Proteins/genetics
6.
Exp Dermatol ; 31(2): 214-222, 2022 02.
Article in English | MEDLINE | ID: mdl-34379845

ABSTRACT

Acral peeling skin syndrome (APSS) is a heterogenous group of genodermatoses, manifested by peeling of palmo-plantar skin and occasionally associated with erythema and epidermal thickening. A subset of APSS is caused by mutations in protease inhibitor encoding genes, resulting in unopposed protease activity and desmosomal degradation and/or mis-localization, leading to enhanced epidermal desquamation. We investigated two Arab-Muslim siblings with mild keratoderma and prominent APSS since infancy. Genetic analysis disclosed a homozygous mutation in SERPINB7, c.796C > T, which is the founder mutation in Nagashima type palmo-plantar keratosis (NPPK). Although not previously formally reported, APSS was found in other patients with NPPK. We hypothesized that loss of SERPINB7 function might contribute to the peeling phenotype through impairment of keratinocyte adhesion, similar to other protease inhibitor mutations that cause APSS. Mis-localization of desmosomal components was observed in a patient plantar biopsy compared with a biopsy from an age- and gender-matched healthy control. Silencing of SERPINB7 in normal human epidermal keratinocytes led to increased cell sheet fragmentation upon mechanical stress. Immunostaining showed reduced expression of desmoglein 1 and desmocollin 1. This study shows that in addition to stratum corneum perturbation, loss of SERPINB7 disrupts desmosomal components, which could lead to desquamation, manifested by skin peeling.


Subject(s)
Keratoderma, Palmoplantar , Serpins , Atrophy , Homozygote , Humans , Keratinocytes/pathology , Keratoderma, Palmoplantar/genetics , Keratoderma, Palmoplantar/pathology , Serine Proteinase Inhibitors , Serpins/genetics , Skin Diseases/congenital
7.
Clin Exp Dermatol ; 47(10): 1895-1897, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36002914

ABSTRACT

Cutis laxa (CL) comprises a heterogeneous group of entities mainly classified as X-linked, autosomal dominant and recessive forms, which differ in severity. We encountered a CL baby with no familial history. We performed targeted exome sequencing, and detected a de novo heterozygous frameshift mutation in the elastin gene of the baby.


Subject(s)
Cutis Laxa , Cutis Laxa/genetics , Elastin/genetics , Exome/genetics , Frameshift Mutation , Humans , Infant , Mutation
8.
J Hum Genet ; 66(8): 831-834, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33580140

ABSTRACT

FGFR3 encodes a transmembrane receptor tyrosine kinase that has six autophosphorylation sites of tyrosine. Among them, Y770 is a negative regulatory site for the downstream signaling of FGFR3. Constitutive active mutations in FGFR3 are involved in human developmental disorders including familial acanthosis nigricans, an autosomal dominant disorder characterized by general hyperpigmentation with mild acanthosis of the epidermis. Here, we report two unrelated cases of familial acanthosis nigricans with a heterozygous c.2302G>T (p.E768*) mutation in FGFR3 (NM_000142.5). FGFR3 mRNA purified from the skin lesion neither showed aberrant splicing nor nonsense-mediated mRNA decay, indicating that the FGFR3 mutant simply lacked the C-terminal 768-806 amino acids including Y770. While all of the known pathogenic mutations were missense mutations in FGFR3 showing autosomal dominant trait, the c.2302G>T mutation of FGFR3 is a unique autosomal dominant nonsense mutation that causes familial acanthosis nigricans probably via loss of negative regulatory autophosphorylation site of FGFR3.


Subject(s)
Acanthosis Nigricans/genetics , Mutation, Missense , Receptor, Fibroblast Growth Factor, Type 3/genetics , Child, Preschool , Chromosome Disorders , Female , Genetic Predisposition to Disease , Genetic Testing , Heterozygote , Humans , Infant
10.
Pediatr Dermatol ; 36(3): 368-371, 2019 May.
Article in English | MEDLINE | ID: mdl-30864170

ABSTRACT

Woolly hair nevus is a rare syndrome that presents as woolly hair in restricted areas of the scalp and may be associated with pigmented macules or epidermal nevus on the body. Here, we report a case of woolly hair nevus, linear pigmentation, and multiple epidermal nevi with a somatic HRAS c.34G>A(p.G12S) mutation.


Subject(s)
Mutation/genetics , Nevus/genetics , Nevus/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Child, Preschool , Humans , Male
11.
Exp Dermatol ; 27(8): 876-883, 2018 08.
Article in English | MEDLINE | ID: mdl-30019465

ABSTRACT

The skin forms a life-sustaining barrier between the organism and the physical environment. The physical barrier of the skin is mainly comprised of the stratum corneum (SC) and tight junctions (TJs). In recent years, there have been significant advances in our understanding of the epidermal TJ function, composition and regulation. In contrast to the SC, TJs are highly dynamic structures. It was discovered that spatiotemporal regulation of dynamic TJ replacement from cell to cell maintains the TJ barrier homeostasis of the skin, despite continuous cellular turnover. This review summarizes current knowledge about how TJ barrier homeostasis is maintained in simple and stratified epithelia, and how diseases and other conditions affect the TJ barrier in the skin.


Subject(s)
Epithelium/physiology , Skin Diseases/metabolism , Skin Physiological Phenomena , Skin/metabolism , Tight Junctions/metabolism , Animals , Dermatitis, Atopic/metabolism , Epidermal Cells/cytology , Epidermis/physiology , Homeostasis , Humans , Intercellular Junctions , Keratinocytes/cytology , Microscopy, Electron , Permeability , Ultraviolet Rays
13.
Am J Hum Genet ; 93(5): 945-56, 2013 Nov 07.
Article in English | MEDLINE | ID: mdl-24207119

ABSTRACT

"Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.


Subject(s)
Keratoderma, Palmoplantar/genetics , Mutation , Serpins/genetics , Adolescent , Adult , Alleles , Asian People/genetics , Child , Child, Preschool , Exome , Female , Humans , Keratoderma, Palmoplantar/pathology , Male , Middle Aged , Pedigree , Young Adult
14.
Neurochem Res ; 41(1-2): 222-30, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26572545

ABSTRACT

In many animal species, the production of new neurons (neurogenesis) occurs throughout life, in a specialized germinal region called the ventricular-subventricular zone (V-SVZ). In this region, neural stem cells undergo self-renewal and generate neural progenitor cells and new neurons. In the olfactory system, the new neurons migrate rostrally toward the olfactory bulb, where they differentiate into mature interneurons. V-SVZ-derived new neurons can also migrate toward sites of brain injury, where they contribute to neural regeneration. Recent studies indicate that two major branches of the Wnt signaling pathway, the Wnt/ß-catenin and Wnt/planar cell polarity pathways, play essential roles in various facets of adult neurogenesis. Here, we review the Wnt signaling-mediated regulation of adult neurogenesis in the V-SVZ under physiological and pathological conditions.


Subject(s)
Cerebral Ventricles/metabolism , Neurons/cytology , Signal Transduction , Wnt Proteins/metabolism , Animals , Cell Differentiation , Cell Movement , Cell Polarity , Cell Proliferation , Mice , beta Catenin/metabolism
16.
J Allergy Clin Immunol ; 134(4): 856-64, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25282566

ABSTRACT

BACKGROUND: The stratum corneum and tight junctions (TJs) form physical barriers in the epidermis. Dendrites of activated Langerhans cells (LCs) extend beyond the TJs to capture external antigens in mice. LCs and inflammatory dendritic epidermal cells (IDECs) are observed in the skin of patients with atopic dermatitis (AD). OBJECTIVE: We sought to investigate the characteristics of LCs and IDECs and the distribution of their antigen capture receptors in relation to TJs in normal and AD skin. METHODS: We characterized the interactions of LCs and IDECs with TJs and the expression patterns of langerin and FcεRI by using whole-mount epidermal sheets from healthy subjects and patients with AD, ichthyosis vulgaris, and psoriasis vulgaris. RESULTS: As in mouse skin, activated LCs penetrate TJs in human skin. The number of LCs with TJ penetration increased approximately 5-fold in erythematous lesional skin of patients with AD but not in nonlesional skin of patients with AD or lesions of patients with ichthyosis vulgaris or psoriasis. In contrast, IDECs localized in the lower part of the epidermis, and their dendrites extended horizontally without penetration through TJs. Although langerin accumulated on the tips of dendrites of activated LCs, FcεRI was expressed diffusely on the cell surfaces on LCs and IDECs in lesional skin from patients with AD. CONCLUSIONS: These findings highlight interesting differences between LCs and IDECs in epidermis of patients with AD, where LCs, but not IDECs, extend dendrites through the TJs, likely to capture antigens from outside the TJ barrier with a polarized distribution of langerin but not FcεRI. These behavioral differences between skin dendritic cells might reflect an important pathophysiology of AD.


Subject(s)
Dendritic Cells/immunology , Dermatitis, Atopic/immunology , Ichthyosis Vulgaris/immunology , Langerhans Cells/immunology , Psoriasis/immunology , Animals , Antigen Presentation , Antigens, CD/genetics , Antigens, CD/metabolism , Cell Movement , Cells, Cultured , Dermatitis, Atopic/complications , Epidermis/pathology , Humans , Ichthyosis Vulgaris/complications , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/metabolism , Mice , Microscopy, Electron, Scanning , Organ Culture Techniques , Psoriasis/complications , Receptors, IgE/genetics , Receptors, IgE/metabolism , Tight Junctions/metabolism , Tight Junctions/pathology , Tight Junctions/ultrastructure , Transcriptome
17.
J Allergy Clin Immunol ; 132(5): 1111-1120.e4, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24060273

ABSTRACT

BACKGROUND: Flaky tail (ma/ma Flg(ft/ft)) mice have a frameshift mutation in the filaggrin (Flg(ft)) gene and are widely used as a model of human atopic dermatitis associated with FLG mutations. These mice possess another recessive hair mutation, matted (ma), and develop spontaneous dermatitis under specific pathogen-free conditions, whereas genetically engineered Flg(-/-) mice do not. OBJECTIVE: We identified and characterized the gene responsible for the matted hair and dermatitis phenotype in flaky tail mice. METHODS: We narrowed down the responsible region by backcrossing ma/ma mice with wild-type mice and identified the mutation using next-generation DNA sequencing. We attempted to rescue the matted phenotype by introducing the wild-type matted transgene. We characterized the responsible gene product by using whole-mount immunostaining of epidermal sheets. RESULTS: We demonstrated that ma, but not Flg(ft), was responsible for the dermatitis phenotype and corresponded to a Tmem79 gene nonsense mutation (c.840C>G, p.Y280*), which encoded a 5-transmembrane protein. Exogenous Tmem79 expression rescued the matted hair and dermatitis phenotype of Tmem79(ma/ma) mice. Tmem79 was mainly expressed in the trans-Golgi network in stratum granulosum cells in the epidermis in both mice and humans. The Tmem79(ma/ma) mutation impaired the lamellar granule secretory system, which resulted in altered stratum corneum formation and a subsequent spontaneous dermatitis phenotype. CONCLUSIONS: The Tmem79(ma/ma) mutation is responsible for the spontaneous dermatitis phenotype in matted mice, probably as a result of impaired lamellar granule secretory system and altered stratum corneum barrier function.


Subject(s)
Codon, Nonsense , Dermatitis, Atopic/genetics , Eczema/genetics , Homozygote , Membrane Proteins/genetics , Animals , Dermatitis, Atopic/metabolism , Disease Models, Animal , Eczema/metabolism , Epithelium/metabolism , Filaggrin Proteins , Gene Expression , Gene Order , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Phenotype , Protein Transport , Skin/metabolism , Skin/pathology
18.
J Dermatol ; 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39133571

ABSTRACT

Acral peeling skin syndrome (APSS; MIM 609796) is a rare genodermatosis characterized by painless focal cutaneous exfoliation of the dorsal hands and feet, typically displaying autosomal recessive inheritance. While cases associated with a founder mutation in TGM5 are relatively common in European Caucasian populations, no APSS cases have been reported from Japan or other East Asian countries. In contrast, Nagashima-type palmoplantar keratosis (NPPK; MIM 615598), caused by variants in SERPINB7, is relatively common in East Asia due to founder mutations. We describe a 27-year-old Japanese woman with spontaneous focal cutaneous exfoliation of the dorsal hand following prolonged glove use, indicative of APSS. Histopathological examination revealed a cleft between the stratum corneum and stratum granulosum and within the horny layer of the epidermis, supporting this diagnosis. However, her mother and maternal uncle exhibited similar symptoms, and there was no reported consanguinity in the patient's parents or grandparents, prompting suspicion of an autosomal dominant genodermatosis. Whole-genome sequencing (WGS) revealed compound heterozygous variants in TGM5 (c.1037G>A and c.684 + 1G>A) as suspected causative variants in the patient, leading to an APSS diagnosis, the first reported in East Asia. On the other hand, her mother and maternal uncle were diagnosed with NPPK due to compound heterozygous pathogenic variants in SERPINB7 (c.796C>T and c.455-1G>A). This case highlights the complexity of diagnosing skin disorders when multiple genodermatoses with similar phenotypes exist within a pedigree. Comprehensive genetic analyses, such as whole-exome sequencing and WGS, are invaluable for identifying causative variants in such complex cases.

19.
J Dermatol Sci ; 115(3): 111-120, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39033075

ABSTRACT

BACKGROUND: Xeroderma pigmentosum (XP) is characterized by photosensitivity that causes pigmentary disorder and predisposition to skin cancers on sunlight-exposed areas due to DNA repair deficiency. Patients with XP group A (XP-A) develop freckle-like pigmented maculae and depigmented maculae within a year unless strict sun-protection is enforced. Although it is crucial to study pigment cells (melanocytes: MCs) as disease target cells, establishing MCs in primary cultures is challenging. OBJECTIVE: Elucidation of the disease pathogenesis by comparison between MCs differentiated from XP-A induced pluripotent stem cells (iPSCs) and healthy control iPSCs on the response to UV irradiation. METHODS: iPSCs were established from a XP-A fibroblasts and differentiated into MCs. Differences in gene expression profiles between XP-A-iPSC-derived melanocytes (XP-A-iMCs) and Healthy control iPSC-derived MCs (HC-iMCs) were analyzed 4 and 12 h after irradiation with 30 or 150 J/m2 of UV-B using microarray analysis. RESULTS: XP-A-iMCs expressed SOX10, MITF, and TYR, and showed melanin synthesis. Further, XP-A-iMCs showed reduced DNA repair ability. Gene expression profile between XP-A-iMCs and HC-iMCs revealed that, numerous gene probes that were specifically upregulated or downregulated in XP-A-iMCs after 150-J/m2 of UV-B irradiation did not return to basal levels. Of note that apoptotic pathways were highly upregulated at 150 J/m2 UV exposure in XP-A-iMCs, and cytokine-related pathways were upregulated even at 30 J/m2 UV exposure. CONCLUSION: We revealed for the first time that cytokine-related pathways were upregulated even at low-dose UV exposure in XP-A-iMCs. Disease-specific iPSCs are useful to elucidate the disease pathogenesis and develop treatment strategies of XP.


Subject(s)
Cell Differentiation , DNA Repair , Induced Pluripotent Stem Cells , Melanocytes , Ultraviolet Rays , Xeroderma Pigmentosum , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/radiation effects , Ultraviolet Rays/adverse effects , Melanocytes/radiation effects , Melanocytes/metabolism , Xeroderma Pigmentosum/genetics , Xeroderma Pigmentosum/metabolism , Xeroderma Pigmentosum/pathology , Cell Differentiation/radiation effects , DNA Repair/radiation effects , Gene Expression Profiling , Cells, Cultured , Melanins/biosynthesis , Melanins/metabolism , Fibroblasts/radiation effects , Fibroblasts/metabolism , Xeroderma Pigmentosum Group A Protein/genetics , Xeroderma Pigmentosum Group A Protein/metabolism , Transcriptome/radiation effects
20.
J Allergy Clin Immunol ; 129(6): 1538-46.e6, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22409988

ABSTRACT

BACKGROUND: Loss-of-function mutations in filaggrin are major predisposing factors for atopic dermatitis. Although various reports suggest a critical role for filaggrin in stratum corneum (SC) barrier formation, the lack of filaggrin-null (Flg(-/-)) mice has hampered detailed in vivo analysis of filaggrin's functions. OBJECTIVE: We sought to generate Flg(-/-) mice and to assess the effect of filaggrin loss on SC barrier function and percutaneous immune responses. METHODS: We generated Flg(-/-) mice using gene targeting and assessed the morphology, hydration, mechanical strength, and antigen permeability of their SC. Percutaneous immune responses were evaluated through irritant- and hapten-induced contact hypersensitivity studies and by measuring humoral responses to epicutaneous sensitization with protein antigen. RESULTS: Newborn Flg(-/-) mice exhibited dry scaly skin. Despite marked decreases in natural moisturizing factor levels, which are filaggrin degradation products, SC hydration and transepidermal water loss were normal. Microscopic analyses suggested premature shedding of SC layers, and indeed, increased desquamation under mechanical stress was demonstrated. Loss of keratin patterns, which are critical for corneocyte stabilization, is likely attributable to fragility in the Flg(-/-) SC. Antigens penetrated the Flg(-/-) SC more efficiently, leading to enhanced responses in hapten-induced contact hypersensitivity and higher serum levels of anti-ovalbumin IgG(1) and IgE. CONCLUSION: Complete filaggrin deficiency led to altered barrier integrity and enhanced sensitization, which are important factors in early-phase atopic dermatitis. Flg(-/-) mice should provide a valuable tool to further explore additional factors the dysfunction of which leads to uncontrolled inflammation in patients with atopic diseases.


Subject(s)
Blood-Aqueous Barrier/metabolism , Epithelium, Corneal/metabolism , Intermediate Filament Proteins/genetics , Skin/immunology , Animals , Filaggrin Proteins , Fluoresceins , Genotype , Intermediate Filament Proteins/deficiency , Keratins/metabolism , Mice , Mice, Knockout , Permeability , Skin/pathology , Skin/ultrastructure
SELECTION OF CITATIONS
SEARCH DETAIL