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/patologíaRESUMEN
Autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma is characterized by the adoption of a white, spongy appearance of affected areas upon exposure to water. After exome sequencing, missense mutations were identified in AQP5, encoding water-channel protein aquaporin-5 (AQP5). Protein-structure analysis indicates that these AQP5 variants have the potential to elicit an effect on normal channel regulation. Immunofluorescence data reveal the presence of AQP5 at the plasma membrane in the stratum granulosum of both normal and affected palmar epidermis, indicating that the altered AQP5 proteins are trafficked in the normal manner. We demonstrate here a role for AQP5 in the palmoplantar epidermis and propose that the altered AQP5 proteins retain the ability to form open channels in the cell membrane and conduct water.
Asunto(s)
Acuaporina 5/genética , Membrana Celular/metabolismo , Epidermis/metabolismo , Queratodermia Palmar y Plantar Difusa/genética , Mutación , Muñeca/fisiopatología , Secuencia de Bases , Epidermis/fisiopatología , Genes Dominantes , Humanos , Queratodermia Palmar y Plantar Difusa/fisiopatología , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Transporte de Proteínas , Agua/metabolismoRESUMEN
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/diagnósticoRESUMEN
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.
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 , FenotipoRESUMEN
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 , ProlinaRESUMEN
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 ADNRESUMEN
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.
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.
RESUMEN
Transgrediens et progrediens palmoplantar keratoderma, known as Greither's syndrome, was originally described in 1952 and is characterized by diffuse keratoderma of the palms and soles, extending to the back aspects (transgrediens) and involving the skin over the Achilles' tendon. Patchy hyperkeratosis also develops on the shins, knees, elbows, and sometimes on the skin flexures. We describe two unrelated families affected with Greither's syndrome, in which the same dominant missense mutation gave rise to the amino acid change N188S in K1. The previously reported cases of Greither's syndrome showed phenotypic variability suggestive of different underlying gene defects. Our findings suggest that at least some cases of Greither's syndrome are caused by keratin mutations.
Asunto(s)
Queratinas/genética , Queratodermia Palmoplantar/genética , Mutación Missense , Adolescente , Femenino , Humanos , Lactante , Queratina-1 , Queratodermia Palmoplantar/diagnóstico , Masculino , Linaje , SíndromeRESUMEN
Defolliculated is a novel spontaneous mouse mutation that maps to chromosome 11 close to the type I keratin locus. Histology shows abnormal differentiation of the sebaceous gland, with the sebocytes producing little or no sebum and undergoing abnormal cornification. The hair follicles fail to regress during catagen leading to abnormally long follicles. In contrast the hair shafts are shorter than normal, suggesting altered differentiation or proliferation of matrix cells during anagen. The shafts emerge from the follicle with cornified material still attached. The dermis contains increased numbers of immune cells, including T cells (CD4-positive), macrophages, and mast cells, at all time points examined. Complete elimination of all pelage and tail follicles occurs after two to three hair cycles, apparently by necrosis. Defolliculated may be a useful model for determining further functions of the sebaceous gland, and for understanding the regulation of catagen and hair follicle immunology.
Asunto(s)
Alopecia/genética , Alopecia/patología , Folículo Piloso/anomalías , Ratones Mutantes/anomalías , Glándulas Sebáceas/anomalías , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Cromosomas , Epidermis/anomalías , Epidermis/inmunología , Epidermis/patología , Genes Dominantes , Folículo Piloso/inmunología , Folículo Piloso/patología , Ratones , Ratones Endogámicos BALB C , Fenotipo , Glándulas Sebáceas/inmunología , Glándulas Sebáceas/patologíaAsunto(s)
Desmoplaquinas/genética , Enfermedades del Cabello/congénito , Enfermedades Cutáneas Genéticas/diagnóstico , Enfermedades Cutáneas Genéticas/genética , Niño , Femenino , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/genética , Enfermedades del Cabello/patología , Homocigoto , Humanos , India , Masculino , Mutación , Enfermedades Cutáneas Genéticas/patología , Adulto JovenRESUMEN
The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and have a crucial role in maintaining epidermal integrity and barrier function. Mutations causing SAM syndrome resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. Our deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect.
Asunto(s)
Dermatitis/genética , Desmogleína 1/genética , Hipersensibilidad/genética , Síndrome Debilitante/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación , Índice de Severidad de la Enfermedad , Síndrome , Síndrome Debilitante/metabolismoRESUMEN
Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22. α- and γ-adaptin-binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Proteínas Portadoras/genética , Haploinsuficiencia , Poroqueratosis/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Mapeo Cromosómico , Citosol/ultraestructura , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación de la Expresión Génica , Células HeLa , Humanos , Queratinocitos/metabolismo , Queratinocitos/patología , Linaje , Poroqueratosis/metabolismo , Unión Proteica , Proteínas/genética , Proteínas/metabolismoRESUMEN
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.
Asunto(s)
Estudios de Asociación Genética , Queratina-16/genética , Mutación/genética , Paquioniquia Congénita/genética , Paquioniquia Congénita/patología , Niño , Preescolar , Femenino , Humanos , Queratodermia Palmoplantar/genética , Masculino , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma. Additional clinical features include oral leukokeratosis, follicular keratosis, and cysts (steatocysts and pilosebaceous cysts). PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17. Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis. A total of 21 previously unreported and 22 known mutations were found. Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B. Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide. More unusual mutations included heterozygous splice site mutations, nonsense mutations, and a 1-bp insertion mutation, leading to a frameshift and premature termination codon. This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC.
Asunto(s)
Queratina-16/genética , Queratina-17/genética , Queratina-6/genética , Paquioniquia Congénita/genética , Análisis Mutacional de ADN , Genes Dominantes , Humanos , Queratodermia Palmoplantar/genética , Mutación , Paquioniquia Congénita/diagnósticoRESUMEN
The palmoplantar keratodermas (PPKs) are a large group of clinically and genetically heterogeneous genodermatoses. The gene defects underlying many PPKs still need to be resolved to facilitate definitive molecular diagnosis and genetic counseling. Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16, or KRT17, cause pachyonychia congenita (PC), characterized by hypertrophic nail dystrophy and other ectodermal features. In PC, focal PPK (FPPK) is the most painful and debilitating phenotypic feature. Some families presenting with FPPK alone, or with minimal nail changes, carry mutations in KRT16; however, most FPPK families do not harbor mutations in any of these keratin genes. Here, we report three unrelated families who presented with familial FPPK with minor or absent nail changes. The four PC/FPPK-related keratin genes were excluded; however, mutational analysis of the recently identified KRT6C gene, encoding keratin K6c, showed heterozygous in-frame deletion mutations in all three kindreds. Affected members of Families 1 and 2 carried the same mutation, p.Asn172del. In Family 3, the mutation p.Ile462-Glu470del co-segregated with the disease. KRT6C was shown to be expressed in the plantar epidermis using reverse transcription-PCR, consistent with the phenotype observed in this tissue. These data expand the genetic testing repertoire for the PPKs.