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2.
Genet Med ; 24(5): 1085-1095, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35168889

RESUMO

PURPOSE: Palmoplantar keratodermas (PPKs) form a group of disorders characterized by thickening of palm and sole skin. Over the past 2 decades, many types of inherited PPKs have been found to result from abnormal expression, processing, or function of adhesion proteins. METHODS: We used exome and direct sequencing to detect causative pathogenic variants. Functional analysis of these variants was conducted using reverse transcription quantitative polymerase chain reaction, immunofluorescence confocal microscopy, immunoblotting, a promoter reporter assay, and chromatin immunoprecipitation. RESULTS: We identified 2 heterozygous variants (c.1226A>G and c.633_634dupGT) in KLF4 in 3 individuals from 2 different unrelated families affected by a dominant form of PPK. Immunofluorescence staining for a number of functional markers revealed reduced epidermal DSG1 expression in patients harboring heterozygous KLF4 variants. Accordingly, human keratinocytes either transfected with constructs expressing these variants or downregulated for KLF4 displayed reduced DSG1 expression, which in turn has previously been found to be associated with PPK. A chromatin immunoprecipitation assay confirmed direct binding of KLF4 to the DSG1 promoter region. The ability of mutant KLF4 to transactivate the DSG1 promoter was significantly decreased when compared with wild-type KLF4. CONCLUSION: Loss-of-function variants in KLF4 cause a novel form of dominant PPK and show its importance in the regulation of epidermal differentiation.


Assuntos
Artrogripose , Ceratodermia Palmar e Plantar , Heterozigoto , Humanos , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/patologia , Sequenciamento Completo do Exoma
3.
J Dermatol ; 49(5): 539-544, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35178744

RESUMO

Nagashima-type palmoplantar keratosis (NPPK) is a diffuse, autosomal recessive, and non-epidermolytic palmoplantar keratosis caused by mutations in the SERPINB7 gene, a member of the serine protease inhibitor superfamily. Genetic studies and case reports suggest that NPPK is the most common palmoplantar keratosis in East Asia but rare in Western countries. This study reports eight NPPK patients in seven pedigrees of the Chinese Han ethnicity with two novel (c.530T>C and c.643A>G) and two recurrent mutations (c.796C>T and c.455G>T) in SERPINB7. The diagnosis of NPPK is now well-defined because of the typical manifestations and pathogenic gene tests. However, its pathomechanism is still obscure, and treatment remains a challenge. This study reviewed all 15 pathogenic mutations and related data in the 1000 Genomes Project to elucidate the founder effect of SERPINB7. Also, several latest cases of NPPK in areas outside East Asia are presented, including France, Finland, and Thailand. Further clinical investigation and genetic studies are crucial for identifying the pathomechanism of NPPK. Also, large-scale control studies are required to determine the safety and curative effects of available therapies.


Assuntos
Ceratodermia Palmar e Plantar , Serpinas , /genética , China , Humanos , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Mutação , Serpinas/genética
4.
J Wound Care ; 31(3): 224-228, 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35199600

RESUMO

Chronic venous skin lesions heal quickly with compression therapy and wound bed preparation. However, there are conditions in which the tissue repair process is more difficult, such as Meleda disease. Meleda disease is a rare genetic pathology, transmitted with an autosomal recessive gene with a prevalence of 1:100 000; it is also called palmoplantar keratoderma. In this pathology, there is a state of chronic inflammation, an alteration of the extracellular matrix and migration of fibroblasts and keratinocytes, which block the proliferative phase of the tissue repair process. Through targeted interventions and the use of bioactive dressings, it is possible to heal the venous ulcer, although this can take a long time. The authors report their experience in relation to a patient with Meleda disease and venous ulceration of seven years.


Assuntos
Ceratodermia Palmar e Plantar , Humanos , Queratinócitos , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Extremidade Inferior
5.
Am J Case Rep ; 23: e935393, 2022 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-35202349

RESUMO

BACKGROUND Annular epidermolytic ichthyosis is a rare form of epidermolytic ichthyosis caused by specific pathogenic variants of KRT1 and KRT10. Classically, it manifests at birth with variable degrees of erythroderma and superficial erosions, which subsequently improve with time. Later, it is characterized by a cyclic history of annular hyperkeratotic erythematous plaques over the trunk and proximal extremities, with or without palmoplantar keratoderma. Greither syndrome, another autosomal dominant disorder of KRT1 mutation, is demonstrated by the diffuse, thick, scaly yellow PPK with transgrediens and erythematous border extending up to the Achilles' tendon, patchy hyperkeratotic plaques over the knees, shins, thighs, elbows, knuckles, and axillary folds. We describe a patient with clinical findings consistent with annular epidermolytic ichthyosis mimicking Greither disease with a likely associated pathogenic variant of KRT1. CASE REPORT A 3-year-old Saudi girl presented with a diffuse palmoplantar keratoderma (PPK) extending to the dorsal aspects of the hands and feet up to the Achilles' tendon, first noticed at the age of 3 months, with a history of recurrent coin-shaped erythematous crusted erosions over the trunk, which were spontaneously healed over time, and an associated history of hyperhidrosis. Patchy hyperkeratotic plaques were noticed upon further examination over the bilateral elbows, axillary folds, and oral commissures. CONCLUSIONS The phenotype of our patient is consistent with the clinical features described for AEI, making the new K1 variant a likely pathogenic variant. When K1 mutation is the causative variant of the disease expression, phenotypically, it can present with Greither-like PPK.


Assuntos
Eritroceratodermia Variável , Hiperceratose Epidermolítica , Ceratodermia Palmar e Plantar , Pré-Escolar , Eritroceratodermia Variável/patologia , Feminino , Humanos , Hiperceratose Epidermolítica/diagnóstico , Hiperceratose Epidermolítica/genética , Hiperceratose Epidermolítica/patologia , Lactente , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Fenótipo , Pele/patologia
6.
J Invest Dermatol ; 142(2): 323-332.e8, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34352264

RESUMO

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.


Assuntos
Desmogleína 1/genética , Desmossomos/patologia , Epiderme/patologia , Ceratodermia Palmar e Plantar/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Desmogleína 1/metabolismo , Caderinas de Desmossomos/metabolismo , Desmossomos/metabolismo , Epiderme/metabolismo , Humanos , Ceratodermia Palmar e Plantar/patologia , Mutação com Perda de Função , Microdomínios da Membrana/metabolismo , Mutação de Sentido Incorreto , Domínios Proteicos/genética , Estabilidade Proteica
7.
Exp Dermatol ; 31(2): 214-222, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34379845

RESUMO

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.


Assuntos
Ceratodermia Palmar e Plantar , Serpinas , Atrofia , Homozigoto , Humanos , Queratinócitos/patologia , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Inibidores de Serino Proteinase , Serpinas/genética , Dermatopatias/congênito
8.
Eur J Med Genet ; 65(3): 104440, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35093605

RESUMO

CEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome is a neuro ichthyotic syndrome characterized by a clinical constellation of features including severe developmental delay, microcephaly, and facial dysmorphism. Here, we report the clinical and molecular characterization of a patient with CEDNIK syndrome harboring two compound heterozygous variants in the SNAP29 gene. The patient presents a combination of a loss-of-function SNAP29 mutation and a ∼370 kb 22q11.2 deletion, each of these genetic variants inherited from one of the parents. This report provides detailed data of a patient with unprecedented genetic events leading to the CEDNIK phenotype and may contribute to the elucidation of this rare condition.


Assuntos
Ceratodermia Palmar e Plantar , Proteínas Qc-SNARE , Brasil , Humanos , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Mutação , Síndromes Neurocutâneas , Fenótipo , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/genética
9.
Eur J Dermatol ; 31(3): 342-350, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34309520

RESUMO

R-spondin (RSPO)1 is a fibroblast-secreted protein that belongs to the R-spondin protein family which is essential for reproductive organ development, epithelial stem cell renewal and cancer induction or suppression. RSPO1 gene mutations cause palmoplantar hyperkeratosis with squamous cell carcinoma (SCC) of the skin, 46XX sex reversal and true hermaphroditism. To characterize RSPO1-deficient skin fibroblasts derived from two patients with mutations in RSPO1, with palmoplantar hyperkeratosis, recurrent SCC and 46XX sex reversal, to provide further insight into disease-related skin tumourigenesis. Fibroblast cultures from non-tumoural palmoplantar skin biopsies were established to evaluate features and properties that may be altered at cancer onset, i.e. proliferation, extracellular matrix contraction and invasion, as well as TGF-ß and matrix metalloproteinase (MMP) secretion. Fibroblasts demonstrated increased proliferative potential in vitro, a high level of collagen contraction and invasion by SCC cells, release of high levels of pro-inflammatory and pro-fibrotic TGF-ß, and increased expression of MMP1 and MMP3. Analysis of the expression of selected proteins associated with RSPO1-activated pathways confirmed sustained activation of the TGF-ß signalling pathway and indicated a loss of TGF-ß inhibitory feedback. Also, treatment of fibroblasts with a recombinant RSPO1 protein aggravated this pro-inflammatory phenotype, suggesting caution in designing therapeutic strategies based on restoration of protein function. Our findings indicate that fibroblasts from RSPO1-mutated patients behave similarly to cancer-associated fibroblasts. Chronic inflammation and fibrotic changes in palmoplantar skin may play a role in SCC development and recurrence, possibly by irreversibly activating the tumourigenic phenotype of fibroblasts.


Assuntos
Fibroblastos/patologia , Ceratodermia Palmar e Plantar/patologia , Mutação , Trombospondinas/genética , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Fenótipo , Transdução de Sinais , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fator de Crescimento Transformador beta/metabolismo
10.
Genes (Basel) ; 12(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067522

RESUMO

Ectodermal dysplasia-syndactyly syndrome 1 (EDSS1) is characterized by cutaneous syndactyly of the toes and fingers and abnormalities of the hair and teeth, variably associated with nail dystrophy and palmoplantar keratoderma (PPK). EDSS1 is caused by biallelic mutations in the NECTIN4 gene, encoding the adherens junction component nectin-4. Nine EDSS1 cases have been described to date. We report a 5.5-year-old female child affected with EDSS1 due to the novel homozygous frameshift mutation c.1150delC (p.Gln384ArgfsTer7) in the NECTIN4 gene. The patient presents brittle scalp hair, sparse eyebrows and eyelashes, widely spaced conical teeth and dental agenesis, as well as toenail dystrophy and mild PPK. She has minimal proximal syndactyly limited to toes 2-3, which makes the phenotype of our patient peculiar as the overt involvement of both fingers and toes is typical of EDSS1. All previously described mutations are located in the nectin-4 extracellular portion, whereas p.Gln384ArgfsTer7 occurs within the cytoplasmic domain of the protein. This mutation is predicted to affect the interaction with afadin, suggesting that impaired afadin activation is sufficient to determine EDSS1. Our case, which represents the first report of a NECTIN4 mutation with toe-only minimal syndactyly, expands the phenotypic and molecular spectrum of EDSS1.


Assuntos
Moléculas de Adesão Celular/genética , Displasia Ectodérmica/genética , Ceratodermia Palmar e Plantar/genética , Sindactilia/genética , Criança , Displasia Ectodérmica/patologia , Feminino , Mutação da Fase de Leitura , Humanos , Ceratodermia Palmar e Plantar/patologia , Sindactilia/patologia , Síndrome , Dedos do Pé/anormalidades
13.
J Invest Dermatol ; 141(8): 1964-1974, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33675791

RESUMO

Gain-of-function mutations in the TRPV3 gene can cause Olmsted syndrome characterized by palmoplantar and periorificial keratoderma, itch, and hair loss. The mechanism underlying the hair loss remains unclear. In this study, we engineered an Olmsted syndrome mouse model by introducing the point mutation G568V to the corresponding Trpv3 locus in the mice. These mice developed fully penetrant hair loss. The hair loss was associated with premature differentiation of follicular keratinocytes characterized by precocious degeneration of trichohyalin and keratins, increased production of deiminated proteins, elevated apoptosis, and attenuation of transcription regulators (Foxn1, Msx2, Dlx3, and Gata3) known to regulate hair follicle differentiation. These abnormalities occurred in the medial‒proximal region of the inner root sheath and the hair shaft, where Trpv3 is highly expressed, and correlated with an impaired formation of the hair canal and the hair shaft. The mutant Trpv3 mice also exhibited increased proliferation in the outer root sheath, accelerated hair cycle, reduction of hair follicle stem cells, and miniaturization of regenerated hair follicles. Findings from this study suggest that precocious maturation of postmitotic follicular keratinocytes drives hair loss in patients with Olmsted syndrome.


Assuntos
Alopecia/genética , Folículo Piloso/patologia , Ceratodermia Palmar e Plantar/complicações , Canais de Cátion TRPV/genética , Alopecia/patologia , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Mutação com Ganho de Função , Folículo Piloso/citologia , Humanos , Queratinócitos/patologia , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Camundongos , Camundongos Transgênicos , Mutação Puntual , Síndrome
14.
J Invest Dermatol ; 141(9): 2229-2237, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33741389

RESUMO

Mal de Meleda is an autosomal recessive palmoplantar keratoderma associated with mutations in a gene encoding SLURP-1. SLURP-1 controls growth, differentiation, and apoptosis of keratinocytes by interaction with α7-type nicotinic acetylcholine receptors. SLURP-1 has a three-finger structure with a ß-structural core (head) and three prolonged loops (fingers). To determine the role of SLURP-1 mutations, we produced 22 mutant variants of the protein, including those involved in Mal de Meleda pathogenesis. All mutants except R71H, R71P, T52A, R96P, and L98P were produced in the folded form. SLURP-1 reduces the growth of Het-1A keratinocytes; thus, we studied the influence of the mutations on its antiproliferative activity. Mutations in loops I and III led to the protein inactivation, whereas most mutations in loop II increased SLURP-1 antiproliferative activity. Alanine substitutions of R96 and L98 residues located in the protein head resulted in the appearance of additional pro-apoptotic activity. Our results agree with the diversity of Mal de Meleda phenotypes. Using obtained functional data, the SLURP-1/α7 type nicotinic acetylcholine receptor complex was modeled in silico. Our study provides functional and structural information about the role of the SLURP-1 mutations in Mal de Meleda pathogenesis and predicts SLURP-1 variants, which could drive the disease.


Assuntos
Antígenos Ly/genética , Queratinócitos/metabolismo , Ceratodermia Palmar e Plantar/metabolismo , Mutação/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Antígenos Ly/metabolismo , Apoptose , Linhagem Celular , Proliferação de Células , Progressão da Doença , Humanos , Queratinócitos/patologia , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Mutagênese Sítio-Dirigida , Fenótipo , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
15.
Biomed Res Int ; 2021: 8841994, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33575348

RESUMO

Nagashima-type palmoplantar keratosis (NPPK) is the most prevalent palmoplantar keratoderma (PPK) in East Asia. Homozygous or compound heterozygous loss-of-function mutations in serpin peptidase inhibitor, clade B (ovalbumin), and member 70 (SERPINB7), which encodes members of the serine protease inhibitor superfamily, have been identified as the cause of NPPK. Clinical manifestations of NPPK include well-demarcated erythema, mild to moderate hyperkeratosis on the whole palm, and sole with transgrediens, extending to the dorsal surfaces of the hands and feet, inner wrists, ankles, and the Achilles tendon areas. In this study, we perform a review of relevant clinical cases aimed at elucidating the clinical characteristics, genetic characterization, differential diagnoses, and clinical management of NPPK. A better understanding of the clinical characteristics and pathogenic gene characterization of NPPK will enhance the diagnosis of NPPK, identify related diseases, and inform on the precise therapy and prognosis. Moreover, it will promote the awareness of NPPK in non-Asian regions.


Assuntos
Ceratodermia Palmar e Plantar , Gerenciamento Clínico , Humanos , Ceratodermia Palmar e Plantar/genética , Ceratodermia Palmar e Plantar/patologia , Ceratodermia Palmar e Plantar/terapia , Mutação , Serpinas/genética
16.
Clin Exp Dermatol ; 46(5): 867-873, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33486795

RESUMO

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 χ2 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.


Assuntos
Queratinas/genética , Ceratodermia Palmar e Plantar/genética , Leucoplasia Oral/genética , Paquioníquia Congênita/complicações , Paquioníquia Congênita/genética , Idade de Início , Estudos de Casos e Controles , Pré-Escolar , Estudos de Coortes , Variação Genética , Heterozigoto , Humanos , Lactente , Queratina-16 , Queratina-17 , Queratina-6 , Ceratodermia Palmar e Plantar/epidemiologia , Ceratodermia Palmar e Plantar/patologia , Ceratose/patologia , Leucoplasia Oral/epidemiologia , Leucoplasia Oral/patologia , Mutação , Doenças da Unha/diagnóstico , Doenças da Unha/epidemiologia , Doenças da Unha/genética , Unhas Malformadas/diagnóstico , Unhas Malformadas/epidemiologia , Unhas Malformadas/genética , Paquioníquia Congênita/classificação , Paquioníquia Congênita/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Sistema de Registros , Índice de Gravidade de Doença
17.
Mol Genet Genomic Med ; 9(2): e1574, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33443819

RESUMO

BACKGROUND: Variants in the GJB2 gene encoding the gap junction protein connexin-26 (Cx26) can cause autosomal recessive nonsyndromic hearing loss or a variety of phenotypically variable autosomal dominant disorders that effect skin and hearing, such as palmoplantar keratoderma (PPK) with deafness and keratitis-ichthyosis-deafness (KID) syndrome. Here, we report a patient with chronic mucocutaneous candidiasis, hyperkeratosis with resorption of the finger tips, profound bilateral sensorineural hearing loss, and normal hair and ocular examination. Exome analysis identified a novel missense variant in GJB2 (NM_004004.5:c.101T>A, p.Met34Lys) that was inherited from a mosaic unaffected parent in the setting of a well-reported GJB2 loss of function variant (NM_004004.5:c.35delG, p.Gly12Valfs*2) on the other allele. METHOD: Rat epidermal keratinocytes were transfected with cDNA encoding wildtype Cx26 and/or the Met34Lys mutant of Cx26. Fixed cells were immunolabeled in order to assess the subcellular location of the Cx26 mutant and cell images were captured. RESULTS: Expression in rat epidermal keratinocytes revealed that the Met34Lys mutant was retained in the endoplasmic reticulum, unlike wildtype Cx26, and failed to reach the plasma membrane to form gap junctions. Additionally, the Met34Lys mutant acted dominantly to wildtype Cx26, restricting its delivery to the cell surface. CONCLUSION: Overall, we show the p.Met34Lys variant is a novel dominant acting variant causing PPK with deafness. The presence of a loss a function variant on the other allele creates a more severe clinical phenotype, with some features reminiscent of KID syndrome.


Assuntos
Conexina 26/genética , Surdez/genética , Ceratodermia Palmar e Plantar/genética , Fenótipo , Adulto , Células Cultivadas , Conexina 26/metabolismo , Surdez/patologia , Feminino , Mutação da Fase de Leitura , Humanos , Queratinócitos/metabolismo , Ceratodermia Palmar e Plantar/patologia , Mutação de Sentido Incorreto , Transporte Proteico
18.
J Invest Dermatol ; 141(4): 722-726, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33080304

RESUMO

The palmoplantar epidermis is a specialized area of the skin that undergoes high levels of mechanical stress. The palmoplantar keratinization and esophageal cancer syndrome, tylosis with esophageal cancer, is linked to mutations in RHBDF2 encoding the proteolytically inactive rhomboid protein, iRhom2. Subsequently, iRhom2 was found to affect palmoplantar thickening to modulate the stress keratin response and to mediate context-dependent stress pathways by p63. iRhom2 is also a direct regulator of the sheddase, ADAM17, and the antiviral adaptor protein, stimulator of IFN genes. In this perspective, the pleiotropic functions of iRhom2 are discussed with respect to the skin, inflammation, and the antiviral response.


Assuntos
Dermatite/imunologia , Epiderme/patologia , Neoplasias Esofágicas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ceratodermia Palmar e Plantar/genética , Dermatopatias Virais/imunologia , Proteína ADAM17/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Dermatite/genética , Modelos Animais de Doenças , Epiderme/imunologia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/patologia , , Regulação da Expressão Gênica/imunologia , Mãos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinas/metabolismo , Ceratodermia Palmar e Plantar/imunologia , Ceratodermia Palmar e Plantar/patologia , Camundongos , Camundongos Knockout , Mutação , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Dermatopatias Virais/genética , Dermatopatias Virais/virologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
19.
Clin Exp Dermatol ; 46(1): 103-108, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32683719

RESUMO

BACKGROUND: Palmoplantar keratoderma (PPK) refers to a large group of disorders characterized by extensive genetic and phenotypic heterogeneity. PPK diagnosis therefore increasingly relies upon genetic analysis. AIM: To delineate the genetic defect underlying a case of diffuse erythematous PPK associated with peeling of the skin. METHODS: Whole exome and direct sequencing, real-time quantitative PCR, protein modelling and a cathepsin B enzymatic assay were used. RESULTS: The patient studied had severe diffuse erythematous PPK transgrediens. Pedigree analysis suggested an autosomal dominant mode of inheritance. Whole exome sequencing revealed a heterozygous missense mutation in the CTSB gene, encoding the cysteine protease cathepsin B. Genomic duplications in a noncoding region, which regulates the expression of CTSB, were recently found to cause erythrokeratolysis hiemalis, a rare autosomal dominant disorder of cornification. This mutation affects a highly conserved residue, and is predicted to be pathogenic. Protein modelling indicated that the mutation is likely to lead to increased endopeptidase cathepsin B activity. Accordingly, the CTSB variant was found to result in increased cathepsin B proteolytic activity. CONCLUSION: In summary, we report the identification of the first gain-of-function missense mutation in CTSB, which was found to be associated in one individual with a dominant form of diffuse PPK.


Assuntos
Catepsina B/genética , Ceratodermia Palmar e Plantar/genética , Mutação de Sentido Incorreto , Adulto , Catepsina B/ultraestrutura , Feminino , Humanos , Ceratodermia Palmar e Plantar/patologia , Masculino , Estrutura Molecular , Linhagem , Pele/patologia , Sequenciamento Completo do Exoma
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