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1.
Hum Mol Genet ; 25(6): 1176-91, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26758872

RESUMEN

Meesmann epithelial corneal dystrophy (MECD) is a rare autosomal dominant disorder caused by dominant-negative mutations within the KRT3 or KRT12 genes, which encode the cytoskeletal protein keratins K3 and K12, respectively. To investigate the pathomechanism of this disease, we generated and phenotypically characterized a novel knock-in humanized mouse model carrying the severe, MECD-associated, K12-Leu132Pro mutation. Although no overt changes in corneal opacity were detected by slit-lamp examination, the corneas of homozygous mutant mice exhibited histological and ultrastructural epithelial cell fragility phenotypes. An altered keratin expression profile was observed in the cornea of mutant mice, confirmed by western blot, RNA-seq and quantitative real-time polymerase chain reaction. Mass spectrometry (MS) and immunohistochemistry demonstrated a similarly altered keratin profile in corneal tissue from a K12-Leu132Pro MECD patient. The K12-Leu132Pro mutation results in cytoplasmic keratin aggregates. RNA-seq analysis revealed increased chaperone gene expression, and apoptotic unfolded protein response (UPR) markers, CHOP and Caspase 12, were also increased in the MECD mice. Corneal epithelial cell apoptosis was increased 17-fold in the mutant cornea, compared with the wild-type (P < 0.001). This elevation of UPR marker expression was also observed in the human MECD cornea. This is the first reporting of a mouse model for MECD that recapitulates the human disease and is a valuable resource in understanding the pathomechanism of the disease. Although the most severe phenotype is observed in the homozygous mice, this model will still provide a test-bed for therapies not only for corneal dystrophies but also for other keratinopathies caused by similar mutations.


Asunto(s)
Distrofia Corneal Epitelial Juvenil de Meesmann/genética , Queratina-12/genética , Queratina-3/genética , Mutación Missense , Adulto , Animales , Apoptosis/genética , Modelos Animales de Enfermedad , Exones , Femenino , Heterocigoto , Humanos , Ratones , Ratones Transgénicos , Mutación , Linaje , Respuesta de Proteína Desplegada
2.
Am J Hum Genet ; 96(3): 440-7, 2015 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-25683118

RESUMEN

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs∗8, p.Lys142∗, and p.Val584Trpfs∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.


Asunto(s)
Proteínas de Unión al Calcio/genética , Queilitis/genética , Queratosis/genética , Mutación , Enfermedades de la Uña/genética , Enfermedades de la Piel/genética , Adulto , Apoptosis/genética , Proteínas de Unión al Calcio/metabolismo , Adhesión Celular/genética , Epidermis/metabolismo , Femenino , Homocigoto , Humanos , Etiquetado Corte-Fin in Situ , Queratinocitos , Masculino , Persona de Mediana Edad , Linaje , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Piel/patología
3.
J Allergy Clin Immunol ; 136(5): 1268-76, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26073755

RESUMEN

BACKGROUND: Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 gene (DSG1). To date, only 3 families have been reported. OBJECTIVE: We studied a new case of SAM syndrome known to have no mutations in DSG1 to detail the clinical, histopathologic, immunofluorescent, and ultrastructural phenotype and to identify the underlying molecular mechanisms in this rare genodermatosis. METHODS: Histopathologic, electron microscopy, and immunofluorescent studies were performed. Whole-exome sequencing data were interrogated for mutations in desmosomal and other skin structural genes, followed by Sanger sequencing of candidate genes in the patient and his parents. RESULTS: No mutations were identified in DSG1; however, a novel de novo heterozygous missense c.1757A>C mutation in the desmoplakin gene (DSP) was identified in the patient, predicting the amino acid substitution p.His586Pro in the desmoplakin polypeptide. CONCLUSIONS: SAM syndrome can be caused by mutations in both DSG1 and DSP. Knowledge of this genetic heterogeneity is important for both analysis of patients and genetic counseling of families. This condition and these observations reinforce the importance of heritable skin barrier defects, in this case desmosomal proteins, in the pathogenesis of atopic disease.


Asunto(s)
Dermatitis/genética , Desmoplaquinas/genética , Hipersensibilidad/genética , Mutación Missense/genética , Síndrome Debilitante/genética , Niño , Preescolar , Análisis Mutacional de ADN , Dermatitis/diagnóstico , Desmogleína 1/genética , Progresión de la Enfermedad , Humanos , Hipersensibilidad/diagnóstico , Lactante , Recién Nacido , Masculino , Linaje , Estructura Terciaria de Proteína/genética , Piel/patología , Síndrome Debilitante/diagnóstico
4.
Nat Genet ; 39(5): 650-4, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17417636

RESUMEN

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.


Asunto(s)
Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Ictiosis Vulgar/genética , Proteínas de Filamentos Intermediarios/genética , Secuencia de Bases , Codón sin Sentido/genética , Epidermis/metabolismo , Proteínas Filagrina , Mutación del Sistema de Lectura/genética , Frecuencia de los Genes , Humanos , Proteínas de Filamentos Intermediarios/metabolismo , Irlanda , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Población Blanca
5.
Cell Tissue Res ; 360(3): 583-9, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25620412

RESUMEN

Mutations in keratin genes cause a diverse spectrum of skin, hair and mucosal disorders. Cutaneous disorders include epidermolysis bullosa simplex, palmoplantar keratoderma, epidermolytic ichthyosis and pachyonychia congenita. Both clinical and laboratory observations confirm a major role for keratins in maintaining epidermal cell-cell adhesion. When normal tissue homeostasis is disturbed, for example, during wound healing and cancer, keratins play an important non-mechanical role. Post-translational modifications including glycosylation and phosphorylation of keratins play an important role in protection of epithelial cells from injury. Keratins also play a role in modulation of the immune response. A current focus in the area of keratins and disease is the development of new treatments including small inhibitory RNA (siRNA) to mutant keratins and small molecules to modulate keratin expression.


Asunto(s)
Queratinas/metabolismo , Enfermedades de la Piel/metabolismo , Animales , Fenómenos Biomecánicos , Enfermedades del Cabello/metabolismo , Enfermedades del Cabello/patología , Enfermedades del Cabello/terapia , Humanos , Queratinas/genética , Mutación/genética , Enfermedades de la Piel/patología , Enfermedades de la Piel/terapia
6.
Nat Genet ; 38(3): 337-42, 2006 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-16444271

RESUMEN

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.


Asunto(s)
Ictiosis Vulgar/genética , Proteínas de Filamentos Intermediarios/genética , Mutación , Niño , Femenino , Proteínas Filagrina , Tamización de Portadores Genéticos , Humanos , Masculino , Linaje , Fosfoproteínas/genética , Valores de Referencia , Eliminación de Secuencia
7.
Nat Genet ; 38(4): 441-6, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16550169

RESUMEN

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.


Asunto(s)
Dermatitis Atópica/genética , Proteínas de Filamentos Intermediarios/fisiología , Mutación , Fenómenos Fisiológicos de la Piel , Alelos , Asma/genética , Asma/inmunología , Niño , Estudios de Cohortes , Dermatitis Atópica/inmunología , Femenino , Proteínas Filagrina , Predisposición Genética a la Enfermedad , Humanos , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/inmunología , Masculino , Linaje
9.
J Am Acad Dermatol ; 66(6): e193-9, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21601946

RESUMEN

BACKGROUND: Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16, or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Available studies assessing oral retinoid treatment for PC are limited to a few case reports. OBJECTIVE: We sought to assess overall effectiveness, adverse effects, and patient perspective in patients with PC receiving oral retinoids. METHODS: In a questionnaire-based retrospective cross-sectional survey of 30 patient with PC assessing oral retinoids (10-50 mg/d for 1-240 months), we determined the clinical score, satisfaction score, visual analog pain scale, and adverse effects. RESULTS: In 50% of patients there was thinning of hyperkeratoses (average improvement 1.6 on a scale from -3 to +3) (95% confidence interval 1.2-1.9, P < .001). In all, 14% observed amelioration of their pachyonychia; 79% did not experience any nail change. The self-reported overall satisfaction score with oral retinoid treatment was 2 or greater in 50% of the patients (mean 4.5 on a scale of 1-10). Although 33% reported decreased and 27% increased plantar pain with treatment, 40% did not notice any pain change. All patients experienced adverse effects, and 83% reported to have discontinued medication. Risk/benefit analysis favored lower retinoid doses (≤25 mg/d) over a longer time period (>5 months), compared with higher doses (>25 mg/d) for a shorter time (≤5 months). LIMITATIONS: The retrospective, cross-sectional study design is prone to a recall bias. CONCLUSION: Oral retinoids are effective in some patients with PC. However, many patients discontinued medication because adverse effects outweighed the benefits. Careful dose titration is warranted in patients informed about potential adverse effects.


Asunto(s)
Fármacos Dermatológicos/uso terapéutico , Paquioniquia Congénita/tratamiento farmacológico , Retinoides/uso terapéutico , Acitretina/uso terapéutico , Administración Oral , Adulto , Estudios Transversales , Fármacos Dermatológicos/administración & dosificación , Fármacos Dermatológicos/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Isotretinoína/uso terapéutico , Masculino , Paquioniquia Congénita/genética , Dimensión del Dolor , Satisfacción del Paciente , Retinoides/administración & dosificación , Retinoides/efectos adversos , Estudios Retrospectivos , Encuestas y Cuestionarios , Resultado del Tratamiento
10.
Indian Dermatol Online J ; 12(1): 147-149, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33768038

RESUMEN

Hidradenitis suppurativa is a chronic relapsing disease with multiple abscesses, nodules, and scars in the apocrine bearing areas. Dowling-Degos is a rare autosomal dominant genodermatosis characterized by multiple hyperpigmented macules or papules in reticulate pattern, affecting mainly the flexures. We report a case of coexisting hidradenitis suppurativa and Dowling-Degos disease in a 31-year-old male in whom PSENEN mutation analysis revealed a splice site mutation c.62-1G>T.

11.
FASEB J ; 23(5): 1366-75, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19124560

RESUMEN

Keratin 7 is expressed in simple epithelia but is expressed at low or undetectable levels in gastrointestinal epithelial cells. In the pancreas, it is present in ductal but not in acinar cells. K7 mRNA is overexpressed in pancreatic cancers. Here we use luciferase reporter assays to analyze the tissue-specific regulatory elements of murine keratin 7 (Krt7) promoter in vitro and in vivo. All elements required for appropriate cell and tissue specificity in reporter assays are present within the Krt7 -234 bp sequence. This fragment appears more selective to pancreatic ductal cells than the Krt19 promoter. GC-rich sequences corresponding to putative Sp1, AP-2 binding sites are essential for in vitro activity. Krt7-LacZ transgenic mice were generated to analyze in vivo activity. Sequences located 1.5 or 0.25 kb upstream of the transcription initiation site drive reporter expression to ductal, but not acinar, cells in transgenic mice. LacZ mRNA was detected in the pancreas as well as in additional epithelial tissues--such as the intestine and the lung--using both promoter constructs. An AdK7Luc adenovirus was generated to assess targeting selectivity in vivo by intravenous injection to immunocompetent mice and in a xenograft model of pancreatic cancer. The -0.25 kb region showed pancreatic selectivity, high activity in pancreatic cancers, and sustained transgene expression in xenografts. In conclusion, the krt7 promoter is useful to target pancreatic ductal adenocarcinoma cells in vitro and in vivo.


Asunto(s)
Queratina-7/genética , Conductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/metabolismo , Regiones Promotoras Genéticas , Transgenes , Adenoviridae/genética , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Transgénicos , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factor de Transcripción Sp1/metabolismo
12.
Eur J Pediatr ; 168(10): 1269-72, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19107515

RESUMEN

Pachyonychia congenita (PC) type 2 is a rare inherited genetic disease characterized by hypertrophic nail dystrophy, palmoplantar hyperkeratosis and multiple pilosebaceous cysts. In some cases, natal teeth and hair abnormalities may be present. It is caused by mutations in keratin 17 or its expression partner keratin 6b. Here, an N92S (p.Asn92Ser) germline keratin 17 gene mutation in a pachyonychia congenita type 2 female patient is presented. The pedigree includes the 15 members of a family who showed a severe expression of the phenotype for six generations with a similar clinical picture consisting of sebaceous cysts, nail dystrophy, hyperkeratosis, hair abnormalities, natal teeth, hoarseness and hyperhydrosis. In conclusion, we emphasize the importance of diagnosing and managing pachyonychia congenita in childhood for the assistance of affected children and for the development of potential therapies.


Asunto(s)
Queratina-17/genética , Mutación , Paquioniquia Congénita/genética , Preescolar , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Paquioniquia Congénita/patología , Linaje , Fenotipo
13.
Pediatr Dermatol ; 26(4): 492-3, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19689542

RESUMEN

Pachyonychia congenita type I is an autosomal dominant disorder where nail abnormalities are a constant feature and develop during childhood. We report here a family with pachyonychia congenita type I and very mild nail changes to underline that this diagnosis should be considered even in the absence of severe nail thickening.


Asunto(s)
Uñas/patología , Paquioniquia Congénita/genética , Paquioniquia Congénita/patología , Adulto , Anciano , Arginina , Progresión de la Enfermedad , Genes Dominantes , Heterocigoto , Humanos , Lactante , Queratina-6/genética , Masculino , Mutación Missense , Onicólisis/genética , Onicólisis/patología , Prolina
14.
J Dermatol Sci ; 51(3): 151-7, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18495438

RESUMEN

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.


Asunto(s)
Paquioniquia Congénita/genética , Paquioniquia Congénita/terapia , ARN Interferente Pequeño/uso terapéutico , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Genéticas/terapia , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Terapia Genética/métodos , Humanos , Queratina-6/genética , Modelos Genéticos , Mutación Puntual , ARN Interferente Pequeño/genética
15.
J Dermatol Sci ; 48(3): 199-205, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17719747

RESUMEN

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant keratin disorder, subdivided into two major variants, PC-1 and PC-2. Predominant characteristics include hypertrophic nail dystrophy, focal palmoplantar keratoderma and oral leukokeratosis. Multiple steatocystomas that develop during puberty are a useful feature distinguishing PC-2 from PC-1. At the molecular level it has been shown that mutations in keratin K6a or K16 cause PC-1 whereas those in K6b or K17 lead to PC-2. OBJECTIVE: To identify mutations in 22 families presenting with clinical symptoms of either PC-1/focal non-epidermolytic palmoplantar keratoderma (FNEPPK) or PC-2. METHODS: Mutation analysis was performed on genomic DNA from PC patients by direct sequencing. RESULTS: Here, we report four new missense and five known mutations in K6a; one new deletion and three previously identified missense mutations in K16; plus one known mutation in K17. CONCLUSION: With one exception, all these heterozygous mutations are within the highly conserved helix boundary motif regions at either end of the keratin rod domain. In one sporadic case, a unique mutation in K16 resulting in deletion of 24bp was found within the central rod domain, in a child with a phenotype predominantly consisting of focal plantar keratoderma. The identification of mutations in cases of PC is prerequisite for future development of gene-specific and/or mutation-specific therapies.


Asunto(s)
Queratina-16/genética , Queratina-17/genética , Queratina-6/genética , Mutación/genética , Paquioniquia Congénita/genética , Eliminación de Gen , Heterocigoto , Humanos , Mutación Missense/genética , Análisis de Secuencia de ADN
16.
J Am Podiatr Med Assoc ; 107(5): 428-435, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29077501

RESUMEN

Plantar keratodermas can arise due to a variety of genetically inherited mutations. The need to distinguish between different plantar keratoderma disorders is becoming increasingly apparent because there is evidence that they do not respond identically to treatment. Diagnosis can be aided by observation of other clinical manifestations, such as palmar keratoderma, more widespread hyperkeratosis of the epidermis, hair and nail dystrophies, or erythroderma. However, there are frequent cases of plantar keratoderma that occur in isolation. This review focuses on the rare autosomal dominant keratin disorder pachyonychia congenita, which presents with particularly painful plantar keratoderma for which there is no specific treatment. Typically, patients regularly trim/pare/file/grind their calluses and file/grind/clip their nails. Topical agents, including keratolytics (eg, salicylic acid, urea) and moisturizers, can provide limited benefit by softening the skin. For some patients, retinoids help to thin calluses but may lead to increased pain. This finding has stimulated a drive for alternative treatment options, from gene therapy to alternative nongenetic methods that focus on novel findings regarding the pathogenesis of pachyonychia congenita and the function of the underlying genes.


Asunto(s)
Queratodermia Palmoplantar/diagnóstico , Queratodermia Palmoplantar/epidemiología , Queratodermia Palmoplantar/terapia , Paquioniquia Congénita/epidemiología , Paquioniquia Congénita/terapia , Comorbilidad , Manejo de la Enfermedad , Femenino , Humanos , Queratodermia Palmoplantar/psicología , Masculino , Paquioniquia Congénita/diagnóstico , Manejo del Dolor , Pronóstico , Calidad de Vida , Medición de Riesgo , Índice de Severidad de la Enfermedad , Rol del Enfermo
17.
Maedica (Bucur) ; 12(2): 123-126, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29090033

RESUMEN

Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder, with unknown prevalence, although it is estimated there are between 2,000 and 10,000 cases of PC worldwide. The International PC Research Registry (IPCRR) has currently identified (as of November 2016) 746 individuals (in 403 families) with genetically confirmed PC. Heterozygous mutations, predominantly missense mutations, in any one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17 cause PC. The predominant clinical findings include plantar keratoderma, plantar pain and variable dystrophy of some or all toenails and/ or fingernails. Oral leukokeratosis, follicular hyperkeratosis, cysts of various types and natal teeth may also be present. We report the first case of genetically confirmed PC from Romania due to a mutation in KRT6A, p.Arg466Pro.

18.
Indian J Dermatol ; 62(4): 422-426, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28794556

RESUMEN

Pachyonychia congenita (PC) is a rare autosomal dominant genetic skin disorder due to a mutation in any one of the five keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. 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 KRT17 were identified in all affected individuals.

19.
J Invest Dermatol ; 126(8): 1770-5, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16810297

RESUMEN

Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.


Asunto(s)
Dermatitis Atópica/genética , Ictiosis Vulgar/genética , Proteínas de Filamentos Intermediarios/genética , Mutación Puntual , Dermatitis Atópica/epidemiología , Salud de la Familia , Femenino , Proteínas Filagrina , Ligamiento Genético , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Ictiosis Vulgar/epidemiología , Irlanda/epidemiología , Masculino , Linaje , Fenotipo , Prevalencia
20.
Ann N Y Acad Sci ; 1082: 56-61, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17145926

RESUMEN

RNA interference offers a novel approach for treating genetic disorders including the rare monogenic skin disorder pachyonychia congenita (PC). PC is caused by mutations in keratin 6a (K6a), K6b, K16, and K17 genes, including small deletions and single nucleotide changes. Transfection experiments of a fusion gene consisting of K6a and a yellow fluorescent reporter (YFP) resulted in normal keratin filament formation in transfected cells as assayed by fluorescence microscopy. Similar constructs containing a single nucleotide change (N171K) or a three-nucleotide deletion (N171del) showed keratin aggregate formation. Mutant-specific small inhibitory RNAs (siRNAs) effectively targeted these sites. These studies suggest that siRNAs can discriminate single nucleotide mutations and further suggest that "designer siRNAs" may allow effective treatment of a host of genetic disorders including PC.


Asunto(s)
Queratinas/genética , Mutación , Paquioniquia Congénita/terapia , ARN Mensajero/antagonistas & inhibidores , ARN Interferente Pequeño/farmacología , Línea Celular Tumoral , Dimerización , Enfermedades Genéticas Congénitas/terapia , Humanos , Queratina-6/genética , Queratinas/antagonistas & inhibidores , Mutagénesis Sitio-Dirigida , Transfección
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