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1.
Dermatol Online J ; 26(2)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32239901

RESUMO

Aplasia cutis congenita (ACC) is a congenital disorder characterized by localized or generalized absence of skin. Bullous aplasia cutis congenita (BACC) is a rare clinical subtype that has few documented reports in the literature. Herein, we present a new case of BACC in which the bulla was unruptured at birth.


Assuntos
Displasia Ectodérmica/patologia , Dermatoses do Couro Cabeludo/patologia , Couro Cabeludo/patologia , Feminino , Humanos , Recém-Nascido , Doenças Raras
3.
Gene ; 733: 144369, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31972311

RESUMO

MAP2K1 encodes mitogen-activated protein kinase 1 (MEK1). Mutations in MAP2K1 lead to continuous activation of MEK/ERK signaling pathway, giving rise to cardio-facio-cutaneous syndrome (CFCS). However, the molecular mechanisms of abnormal activation of MEK/ERK signaling pathway and the role of autophagy, if any, in manifesting CFCS in MAP2K mutants remain unclear. Here, we report three Chinese children with CFCS having MAP2K1 pathogenic variants, identified by exome sequencing. They presented with dysmorphic facial features, seizures, psychomotor retardation, and short stature. Additionally, the third child showed pulmonary valve stenosis, multiple skeletal deformities, and osteoporosis. Whole exome sequencing revealed two heterozygous missense mutations in exon 3 of MAP2K1 (c.383G>T; p.Gly128Val and c.389A>G; p.Tyr130Cys), as well as a novel heterozygous missense variant (c.170A>T; p.Lys57Met) in exon 2 of MAP2K1. In SH-SY5Y cells, we identified, for the first time, that MAP2K1 mutations can activate the p-ERK-dependent cell cycle progression and autophagy, and cause CFCS. Our results extended the mutational spectrum of MAP2K1, examined the role of MEK1 protein in nerve cell functions, and demonstrated, for the first time, that autophagy may mediate the altered MAP2K1 function, leading to CFCS phenotypes.


Assuntos
Autofagia , Displasia Ectodérmica/patologia , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , MAP Quinase Quinase 1/genética , Mutação , Adulto , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Criança , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/metabolismo , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Humanos , Lactente , Sistema de Sinalização das MAP Quinases , Masculino , Fenótipo , Fosforilação , Células Tumorais Cultivadas
5.
J Dermatol ; 46(8): 734-738, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31180149

RESUMO

We report two cases of aplasia cutis congenita associated with hair collar signs and hemangioma simplex in their parietal regions. A hair collar sign and a hemangioma are known to suggest the possibility of underlying neural tube defects. However, no obvious bone defects or heterotopic neural tissue were observed in the imaging and histopathological examinations. Nevertheless, some pathological observations similar in both cases suggested abnormalities in the process of ectodermal fusion. A flat epidermis and a lack of appendages were recognized. Both cases also exhibited the presence of melanocytes in a portion of the superficial dermal layer. An increase in the number of macrophages was observed in the dermal area with neither elastic fibers nor normal collagen fibers. The peripheral hair follicles grew horizontally.


Assuntos
Displasia Ectodérmica/diagnóstico , Hemangioma/diagnóstico , Macrófagos/patologia , Neoplasias Cutâneas/diagnóstico , Dermoscopia , Displasia Ectodérmica/complicações , Displasia Ectodérmica/patologia , Feminino , Folículo Piloso/diagnóstico por imagem , Folículo Piloso/patologia , Hemangioma/complicações , Hemangioma/patologia , Humanos , Lactente , Melanócitos , Couro Cabeludo , Pele/citologia , Pele/diagnóstico por imagem , Pele/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia
6.
Clin Exp Dermatol ; 44(6): 606-612, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31074523

RESUMO

Pachyonychia congenita (PC) describes a group of genodermatoses manifesting as thickened nails, palmoplantar keratoderma (PPK) and increased risk of cutaneous infections. PC tarda (PCT) describes late-onset PC, and associated genetic polymorphisms have been identified. There has been discussion that PCT may not be a distinct entity but rather misdiagnosed ectodermal dysplasia (ED) or PPK. Clarification of this is important for appropriate diagnosis, management and patient and genetic counselling. We aimed to conduct a systematic review of all reported cases of PCT in the published literature and collate evidence of genetic polymorphisms and clinical features to compare with known features of PC, ED and PPK. PubMed (1946 to 1 July 2018), Scopus (1955 to 1 July 2018) and Web of Science (1990 to 1 July 2018) databases were searched for case reports of PCT with no search restrictions on date or language. The search strategy included the terms pachyonychia congenita tarda OR pachyonychia congenita AND (late onset OR delayed OR PCT). In total, 13 reports describing 19 individual cases of PCT were identified. Of the three identified genetic polymorphisms, the earliest identified has been shown to be highly probably pathogenic, with the second likely to result in a benign amino acid change, while the third has since been shown to be nonpathogenic,. No epigenetic studies have been performed on any reported cases. Previous authors have suggested that a number of cases of PCT may be misdiagnosed ED or PPK. The findings of our review cannot refute this suggestion, and highlight the need for thorough clinical documentation of suspected cases of PCT and thorough genetic screening of kindred to identify causative genetic polymorphisms. Further high-quality datasets and reporting are needed to give further insight into the nature of PCT as a unique entity.


Assuntos
Doenças da Unha/patologia , Unhas Malformadas/patologia , Paquioníquia Congênita/patologia , Adolescente , Adulto , Criança , Erros de Diagnóstico , Displasia Ectodérmica/patologia , Feminino , Humanos , Ceratodermia Palmar e Plantar/patologia , Masculino , Pessoa de Meia-Idade , Doenças da Unha/genética , Unhas Malformadas/genética , Paquioníquia Congênita/diagnóstico , Paquioníquia Congênita/genética , Polimorfismo Genético , Adulto Jovem
7.
Mol Genet Genomic Med ; 7(6): e704, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31050217

RESUMO

BACKGROUND: Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate (EEC) syndrome and Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome belong to p63 syndromes, a group of rare disorders exhibiting a wide variety of clinical manifestations. TP63 mutations have been reported to be associated with both EEC and AEC. METHODS: Analysis of whole exome sequencing (WES) from patients with EEC or AEC syndrome and Sanger sequencing from family members. RESULTS: We confirmed that three Chinese pedigrees affected with EEC or AEC harboring a distinct TP63 mutation, and described novel clinical phenotypes of EEC and AEC, including the presence of cubitus valgus deformity and taurodontism, which were discordant to their classical disease features. We also analyzed the genotype-phenotype correlation based on our findings. CONCLUSION: We reported that the cubitus valgus deformity in patients with EEC and severe taurodontism in a patient with AEC had not been mentioned previously. Our study expands the phenotypic spectrum of EEC and AEC syndrome.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Anormalidades do Olho/genética , Pálpebras/anormalidades , Fenótipo , Dente/patologia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Fenda Labial/patologia , Fissura Palatina/patologia , Displasia Ectodérmica/patologia , Anormalidades do Olho/patologia , Pálpebras/patologia , Feminino , Genótipo , Humanos , Masculino , Mutação , Linhagem
8.
Am J Med Genet A ; 179(8): 1415-1419, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31119873

RESUMO

Incontinentia Pigmenti (IP; MIM 308300) is an X-linked dominant genodermatosis caused by pathogenic variant in IKBKG. The phenotype in adults is poorly described compared to that in children. Questionnaire survey of 99 affected women showed an age at diagnosis from newborn to 41 years, with 53 diagnosed by 6 months of age and 30 as adults. Stage I, II, and III lesions persisted in 16%, 17%, and 71%, respectively, of those who had ever had them. IP is allelic to two forms of ectodermal dysplasia. Many survey respondents reported hypohidrosis and/or heat intolerance and most had Stage IV findings. This suggests that "Stage IV" may be congenitally dysplastic skin that becomes more noticeable with maturity. Fifty-one had dentures or implants with 26 having more invasive jaw or dental surgery. Half had wiry or uncombable hair. Seventy-three reported abnormal nails with 27 having long-term problems. Cataracts and retinal detachment were the reported causes of vision loss. Four had microphthalmia. Respondents without genetic confirmation of IP volunteered information suggesting more involved phenotype or possibly misassigned diagnosis. Ascertainment bias likely accounts for the low prevalence of neurocognitive problems in the respondents.


Assuntos
Catarata/genética , Displasia Ectodérmica/genética , Quinase I-kappa B/genética , Incontinência Pigmentar/genética , Mutação , Descolamento Retiniano/genética , Adolescente , Adulto , Idoso , Catarata/diagnóstico , Catarata/metabolismo , Catarata/patologia , Implantes Dentários , Dentaduras , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patologia , Feminino , Expressão Gênica , Cabelo/metabolismo , Cabelo/patologia , Humanos , Quinase I-kappa B/deficiência , Incontinência Pigmentar/diagnóstico , Incontinência Pigmentar/metabolismo , Incontinência Pigmentar/patologia , Pessoa de Meia-Idade , Unhas/metabolismo , Unhas/patologia , Fenótipo , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia , Índice de Gravidade de Doença , Pele/metabolismo , Pele/patologia , Inquéritos e Questionários , Dente/metabolismo , Dente/patologia
10.
J Hum Genet ; 64(5): 499-504, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30842599

RESUMO

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.


Assuntos
Sequência de Aminoácidos , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Deleção de Sequência , Pré-Escolar , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , Humanos , Leucina , Masculino , Índice de Gravidade de Doença
11.
Am J Med Genet C Semin Med Genet ; 181(2): 208-217, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30896080

RESUMO

RASopathies are a group of genetic disorders due to dysregulation of the RAS-MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety-one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well-known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re-evaluation of the current tumor surveillance recommendation maybe warranted.


Assuntos
Mutação , Fenótipo , Proteínas ras/genética , Síndrome de Costello/genética , Síndrome de Costello/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Hong Kong , Humanos , Síndrome LEOPARD/genética , Síndrome LEOPARD/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Estudos Retrospectivos
12.
Mol Genet Genomic Med ; 7(5): e625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891959

RESUMO

BACKGROUND: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies. METHODS: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism. RESULTS: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids. CONCLUSION: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.


Assuntos
Cisto Dermoide/genética , Displasia Ectodérmica/genética , Oftalmopatias/genética , Lipomatose/genética , Síndromes Neurocutâneas/genética , Nevo Sebáceo de Jadassohn/genética , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cisto Dermoide/patologia , Displasia Ectodérmica/patologia , Oftalmopatias/patologia , GTP Fosfo-Hidrolases/genética , Humanos , Lipomatose/patologia , Proteínas de Membrana/genética , Mosaicismo , Síndromes Neurocutâneas/patologia , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
13.
J Dermatol ; 46(5): 422-425, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30809829

RESUMO

A Chinese female infant presented with ectodermal dysplasia, cleft palate and severe skin erosions at birth. Although all the typical clinical features of ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome were present, the ankyloblepharon was not very marked. We misdiagnosed epidermolysis bullosa and congenital ichthyosiform erythroderma at first and confirmed the diagnosis of AEC syndrome only when she presented with the typical clinical manifestation of recurrent infected scalp erosions at 1 year of age. Mutation analysis of exon 13 of the p63 gene revealed a missense mutation Ile482Thr (c.1445T>C) in the sterile alpha motive domain. In this work we review the clinical features, differential diagnosis and prognosis in AEC syndrome.


Assuntos
Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Erros de Diagnóstico , Displasia Ectodérmica/diagnóstico , Epidermólise Bolhosa/diagnóstico , Anormalidades do Olho/diagnóstico , Pálpebras/anormalidades , Eritrodermia Ictiosiforme Congênita/diagnóstico , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Biópsia , Fenda Labial/genética , Fenda Labial/patologia , Fenda Labial/terapia , Fissura Palatina/genética , Fissura Palatina/patologia , Fissura Palatina/terapia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Displasia Ectodérmica/terapia , Epidermólise Bolhosa/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/terapia , Pálpebras/patologia , Feminino , Testes Genéticos , Heterozigoto , Humanos , Eritrodermia Ictiosiforme Congênita/patologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Mutação de Sentido Incorreto , Pele/patologia
14.
Stem Cell Res ; 34: 101379, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605838

RESUMO

EDA is a gene located at Xq13.1. It encodes different isoforms of tumor necrosis factor (TNF) superfamily member ectodysplasin A. Ectodysplasin A is a transmembrane protein which can be cleaved to form a secreted form and interact with EDA receptor to mediate the development of ectoderm. Mutations of the EDA gene are related to ectodermal dysplasia and tooth agenesis. Here, we report the establishment of the EDA gene knockout human embryonic stem (hES) cell line by CRISPR-Cas9 technology. This cell line provides good materials for further studies of the roles ectodysplasin A plays in ectoderm differentiation and tooth development.


Assuntos
Sistemas CRISPR-Cas/genética , Técnicas de Cultura de Células/métodos , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Técnicas de Inativação de Genes , Células-Tronco Embrionárias Humanas/citologia , Linhagem Celular , Humanos , Masculino
17.
Eur J Med Genet ; 62(9): 103539, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30240710

RESUMO

A 5,6 Mb de novo 19q12-q13.12 interstitial deletion was diagnosed prenatally by array-comparative genomic hybridization in a 26 weeks male fetus presenting with intra-uterine growth retardation, left clubfoot, atypical genitalia and dysmorphic features. Autopsic examination following termination of pregnancy identified a severe disorder of sex development (DSD) including hypospadias, micropenis, bifid scrotum and right cryptorchidism associated with signs of ectodermal dysplasia: scalp hypopigmentation, thick and frizzy hair, absence of eyelashes, poorly developed nails and a thin skin with prominent superficial veins. Other findings were abnormal lung lobation and facial dysmorphism. This new case of DSD with a 19q12q13 deletion expands the phenotypic spectrum associated with this chromosomal rearrangment and suggests that WTIP is a strong candidate gene involved in male sex differentiation.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 19/genética , Transtornos do Desenvolvimento Sexual/genética , Displasia Ectodérmica/genética , Retardo do Crescimento Fetal/genética , Deleção de Genes , Adulto , Transtornos Cromossômicos/patologia , Proteínas Correpressoras/genética , Proteínas do Citoesqueleto/genética , Transtornos do Desenvolvimento Sexual/patologia , Displasia Ectodérmica/patologia , Feminino , Retardo do Crescimento Fetal/patologia , Humanos , Masculino , Gravidez
18.
J Clin Invest ; 129(2): 583-597, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30422821

RESUMO

X-linked dominant incontinentia pigmenti (IP) and X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are caused by loss-of-function and hypomorphic IKBKG (also known as NEMO) mutations, respectively. We describe a European mother with mild IP and a Japanese mother without IP, whose 3 boys with EDA-ID died from ID. We identify the same private variant in an intron of IKBKG, IVS4+866 C>T, which was inherited from and occurred de novo in the European mother and Japanese mother, respectively. This mutation creates a new splicing donor site, giving rise to a 44-nucleotide pseudoexon (PE) generating a frameshift. Its leakiness accounts for NF-κB activation being impaired but not abolished in the boys' cells. However, aberrant splicing rates differ between cell types, with WT NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in induced pluripotent stem cell-derived (iPSC-derived) macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells. Finally, SRSF6 binds to the PE, facilitating its inclusion. Moreover, SRSF6 knockdown or CLK inhibition restores WT NEMO expression and function in mutant cells. A recurrent deep intronic splicing mutation in IKBKG underlies a purely quantitative NEMO defect in males that is most severe in leukocytes and can be rescued by the inhibition of SRSF6 or CLK.


Assuntos
Displasia Ectodérmica , Mutação da Fase de Leitura , Quinase I-kappa B , Incontinência Pigmentar , Íntrons , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Quinase I-kappa B/deficiência , Quinase I-kappa B/metabolismo , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/patologia , Incontinência Pigmentar/genética , Incontinência Pigmentar/metabolismo , Incontinência Pigmentar/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino
19.
Small GTPases ; 10(3): 210-217, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-28287327

RESUMO

DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation. Strikingly, although most other DOCK family proteins are deployed on the plasma membrane, here we show that DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. ER localization of DOCK6 opens up new insights into its functions.


Assuntos
Membrana Celular/metabolismo , Citocinas/metabolismo , Retículo Endoplasmático/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Ubiquitinas/metabolismo , Membrana Celular/genética , Citocinas/genética , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patologia , Retículo Endoplasmático/genética , Técnicas de Silenciamento de Genes , Fatores de Troca do Nucleotídeo Guanina/genética , Células HeLa , Humanos , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/metabolismo , Deformidades Congênitas dos Membros/patologia , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/metabolismo , Dermatoses do Couro Cabeludo/patologia , Ubiquitinas/genética , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
20.
Clin Genet ; 95(1): 85-94, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29767458

RESUMO

The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important in the development of most organs. Mutations in genes encoding components of the NOTCH signalling pathway lead to a spectrum of congenital disorders. Over the past decades, mutations in human NOTCH signalling genes have been identified in several diseases with cardiovascular involvement. NOTCH1 mutations have been described in bicuspid aortic valve disease, left-sided congenital heart disease, and Adams-Oliver syndrome. NOTCH2 mutations lead to the development of Alagille syndrome, while mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To date, mutations in NOTCH4 have not been associated with cardiovascular disease. This review focuses on the mutations described in NOTCH1, NOTCH2, and NOTCH3 and their associated cardiovascular phenotypes.


Assuntos
Doenças Cardiovasculares/genética , Receptor Notch1/genética , Receptor Notch2/genética , Receptor Notch3/genética , Síndrome de Alagille/genética , Síndrome de Alagille/patologia , CADASIL/genética , CADASIL/patologia , Doenças Cardiovasculares/patologia , Proliferação de Células/genética , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Humanos , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Mutação , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologia
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