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1.
Am J Hum Genet ; 108(1): 134-147, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33340455

RESUMO

The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1-7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences ("N-end rule"). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.


Assuntos
Epilepsia/genética , Hipotireoidismo/genética , Transtornos do Neurodesenvolvimento/genética , Receptores Notch/genética , Transdução de Sinais/genética , Ubiquitina-Proteína Ligases/genética , Animais , Anus Imperfurado/genética , Caenorhabditis elegans/genética , Linhagem Celular , Displasia Ectodérmica/genética , Transtornos do Crescimento/genética , Células HEK293 , Perda Auditiva Neurossensorial/genética , Histonas/genética , Humanos , Deficiência Intelectual/genética , Camundongos , Mutação/genética , Nariz/anormalidades , Pancreatopatias/genética , Complexo de Endopeptidases do Proteassoma/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(11): 1265-1268, 2020 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-33179236

RESUMO

OBJECTIVE: To explore the genetic cause of a patient suspected for congenital ectodermal dysplasia with repeated hyperthermia and to assess the reproductive risk for his family. METHODS: Medical whole-exome sequencing (WES) were used to detect single-nucleotide variations and low-coverage massively parallel copy number variation sequencing (CNV-seq) were employed to verify suspected CNVs. PCR and real-time quantitative PCR were applied to confirm the deletion of EDA gene. RESULTS: The results of WES suggested that the patient carried a hemizygous deletion for chrX:69 243 016-69 395 730. CNV-seq indicated that the patient carried a deletion of approximately 0.12 Mb on Xq13.1, which encompassed the EDA gene. The PCR results confirmed that there was a hemizygous deletion of exons 3 to 8 of the EDA gene. The same deletion was not found in his mother. CONCLUSION: The congenital ectodermal dysplasia of the patient may be attributed to deletion of exons 3 to 8 of the EDA gene, which could be de novo or derive from germline mosaicism of his mother. The WES and CNV-seq are of great value for the diagnosis of rare diseases.


Assuntos
Variações do Número de Cópias de DNA , Displasia Ectodérmica , Sequenciamento Completo do Exoma , Displasia Ectodérmica/genética , Ectodisplasinas/genética , Éxons , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mosaicismo , Deleção de Sequência
3.
Medicine (Baltimore) ; 99(44): e22816, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126320

RESUMO

RATIONALE: Ectrodactyly ectodermal dysplasia-cleft lip/palate (EEC) syndrome, limb-mammary syndrome (LMS), and acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome are caused by a TP63 gene disorder and have similar features. In the present article, a R319H mutation in TP63 is reported, and the correlation between genotype and phenotype is discussed based on the current case and previous literature. PATIENT CONCERNS: A 13-year-old Japanese boy had ectrodactyly in the right hand and left foot and syndactyly in the left and right foot, and tooth shape abnormalities. DIAGNOSES: Peripheral blood samples were obtained, and mutation analysis was performed. A heterozygous G>A transition at cDNA position 956 of the TP63 gene was found. The patient was diagnosed with ELA (EEC/LM/ADULT) syndrome based on his clinical features and mutation analysis results. INTERVENTIONS: The patient underwent surgery to correct the left foot malformation at 1 year of age and the right foot syndactyly at 11 years of age. OUTCOMES: No complications were observed after the first and second operations. He can walk comfortably after them, and no additional interventions will be planned in him. We continued to follow up with him up to the present. LESSONS: The concept of ELA syndrome, which is the original concept of combining 3 syndromes (EEC syndrome/LMS/ADULT syndrome) into a unique clinical entity, can help clinicians to better understand TP63-related syndromes and improve the differential diagnosis of these syndromes.


Assuntos
Anodontia/sangue , Mama/anormalidades , Fissura Palatina/sangue , Displasia Ectodérmica/sangue , Dedos/anormalidades , Deformidades Congênitas da Mão/sangue , Obstrução dos Ductos Lacrimais/sangue , Deformidades Congênitas dos Membros/sangue , Unhas Malformadas/sangue , Transtornos da Pigmentação/sangue , Fatores de Transcrição/análise , Proteínas Supressoras de Tumor/análise , Adolescente , Anodontia/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Deformidades Congênitas da Mão/genética , Humanos , Japão , Obstrução dos Ductos Lacrimais/genética , Deformidades Congênitas dos Membros/genética , Masculino , Mutação/genética , Unhas Malformadas/genética , Transtornos da Pigmentação/genética , Fatores de Transcrição/sangue , Proteínas Supressoras de Tumor/sangue
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 567-569, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335888

RESUMO

OBJECTIVE: To explore the genotype-phenotype correlation of Cardio-facio-cutaneous syndrome (CFCS) caused by MAP2K1 gene variants. METHODS: Genomic DNA was extracted from peripheral blood sample from a child patient and his parents. Whole exome sequencing (WES) was carried out for the patient. Suspected variant was verified by Sanger sequencing. RESULTS: The patient was a 1-year-8-month old Chinese male who manifested short stature, psychomotor retardation, relative macrocephaly, distinctive facial features, and congenital heart disease. WES test revealed a heterozygous missense c.389A>G (p.Tyr130Cys) variant in the MAP2K1 gene. Sanger sequencing has confirmed the variant as de novo. According to ACMG/AMP guidelines, the variant was classified as pathogenic. CONCLUSION: Compared with previously reported CFCS cases due to MAP2K1 variants. The patient showed obvious behavioral problems, good appetite and tricuspid regurgitation, which may to be novel features for CFCS.


Assuntos
Displasia Ectodérmica , Facies , Insuficiência de Crescimento , Variação Genética , Cardiopatias Congênitas , MAP Quinase Quinase 1 , China , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Heterozigoto , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Mutação , Sequenciamento Completo do Exoma
5.
Anesth Prog ; 67(1): 45-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191511

RESUMO

Cardiofaciocutaneous (CFC) syndrome is a rare condition characterized by congenital heart disease, craniofacial dysmorphology, and dermatological abnormalities. CFC syndrome is one of the RASopathies, a family of syndromes that also includes Noonan and Costello syndromes, all with underlying gene mutations involving the Ras/mitogen-activated protein kinase pathways. Important considerations for anesthesiologists caring for these patients include the need to evaluate for possible cardiac defects, anticipating and planning for potentially difficult airway management, and the consideration of potential weakness of the respiratory muscles. Musculoskeletal abnormalities, such as muscle weakness and decreased muscle mass, are observed in all RASopathies, but are particularly prominent in CFC syndrome. In patients with CFC syndrome who experience respiratory muscle weakness, the use of desflurane and remifentanil may aid in a faster recovery and effectively help reduce the risk of respiratory complications, such as respiratory depression, following general anesthesia because of their rapid metabolism or elimination.


Assuntos
Anestésicos , Displasia Ectodérmica , Cardiopatias Congênitas , Síndrome de Noonan , Criança , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento , Cardiopatias Congênitas/genética , Humanos
6.
DNA Cell Biol ; 39(5): 783-789, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32129674

RESUMO

Adams-Oliver syndrome (AOS) is a rare hereditary disorder characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects. The etiology of AOS has remained largely unknown, although mutations in the notch receptor 1 (NOTCH1) gene are most common genetic alteration associated with this disease. In this study, we aimed to identify the case of a 6-year-old boy, who presented with large ACC of the scalp and aortic valve stenosis, suggesting the possibility of AOS. Whole-exome sequencing identified a novel, de novo, in-frame deletion in the NOTCH1 gene (NOTCH1 c.1292_1294del, p.Asn431del) in the patient. The p.Asn431del variant was evaluated by several in silico analyses, which predicted that the mutant was likely to be pathogenic. In addition, molecular modeling with the PyMOL Molecular Graphics System suggested that the NOTCH1-N431del destabilizes calcium ion chelation, leading to decreased receptor-ligand binding efficiency. Quantitative reverse transcription PCR showed further significant downregulation of the Notch target genes, hes-related family bHLH transcription factor with YRPW motif 1 (HEY1) and hes family bHLH transcription factor 1 (HES1), suggesting that this mutation causes disease through dysregulation of the Notch signaling pathway. Our study provides evidence that the NOTCH1-N431del mutation is responsible for this case of AOS. To our knowledge, this is the first report of a patient with AOS caused by NOTCH1 mutation in Asia, and this information will be useful for providing the family with genetic counseling that can help to guide their future plans.


Assuntos
Displasia Ectodérmica/genética , Mutação da Fase de Leitura , Deformidades Congênitas dos Membros/genética , Receptor Notch1/genética , Dermatoses do Couro Cabeludo/congênito , Sequência de Aminoácidos , Animais , Sequência de Bases , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , China , Humanos , Masculino , Modelos Moleculares , Conformação Proteica , Receptor Notch1/química , Proteínas Repressoras/genética , Dermatoses do Couro Cabeludo/genética , Fatores de Transcrição HES-1/genética
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 139-141, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034739

RESUMO

OBJECTIVE: To detect potential variant in a male fetus suspected for Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC) syndrome. METHODS: Peripheral blood samples of the fetus and his parents were collected for the extraction of DNA. Whole-exome sequencing was carried out to detect potential variants. Suspected variants were verified by Sanger sequencing. RESULTS: The fetus was found to carry a heterozygous c.673C>T missense variant of the Tp63 gene, which was known to underlie split-hand/split-foot malformation. The same variant was not found in either parents. CONCLUSION: The heterozygous c.673C>T missense variant of the Tp63 gene probably underlies the EEC syndrome in the fetus. Above finding also expanded the phenotypic spectrum for this variant.


Assuntos
Fenda Labial , Fissura Palatina , Displasia Ectodérmica , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Humanos , Deformidades Congênitas dos Membros , Masculino , Sequenciamento Completo do Exoma
8.
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
9.
Orphanet J Rare Dis ; 14(1): 281, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796081

RESUMO

BACKGROUND: Ectodermal dysplasias (ED) are a group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives. An attenuated phenotype is considered a non-syndromic trait when the patient is affected by only one impaired ectodermal structure, such as in non-syndromic tooth agenesis (NSTA) disorder. Hypohidrotic ectodermal dysplasia (HED) is the most highly represented ED. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common subtype, with an incidence of 1/50,000-100,000 males, and is associated with the EDA gene (Xq12-q13.1); the dominant and recessive subtypes involve the EDAR (2q13) and EDARADD (1q42.3) genes, respectively. The WNT10A gene (2q35) is associated more frequently with NSTA. Our goal was to determine the mutational spectrum in a cohort of 72 Spanish patients affected by one or more ectodermal derivative impairments referred to as HED (63/72) or NSTA (9 /72) to establish the prevalence of the allelic variants of the four most frequently associated genes. Sanger sequencing of the EDA, EDAR, EDARADD and WNT10A genes and multiplex ligation-dependent probe amplification (MLPA) were performed. RESULTS: A total of 61 children and 11 adults, comprising 50 males and 22 females, were included. The average ages were 5.4 and 40.2 years for children and adults, respectively. A molecular basis was identified in 51/72 patients, including 47/63 HED patients, for whom EDA was the most frequently involved gene, and 4/9 NSTA patients, most of whom had variants of WNT10A. Among all the patients, 37/51 had variants of EDA, 8/51 had variants of the WNT10A gene, 4/51 had variants of EDAR and 5/51 had variants of EDARADD. In 42/51 of cases, the variants were inherited according to an X-linked pattern (27/42), with the remaining showing an autosomal dominant (10/42) or autosomal recessive (5/42) pattern. Among the NSTA patients, 3/9 carried pathogenic variants of WNT10A and 1/9 carried EDA variants. A total of 60 variants were detected in 51 patients, 46 of which were different, and out of these 46 variants, 12 were novel. CONCLUSIONS: This is the only molecular study conducted to date in the Spanish population affected by ED. The EDA, EDAR, EDARADD and WNT10A genes constitute the molecular basis in 70.8% of patients with a 74.6% yield in HED and 44.4% in NSTA. Twelve novel variants were identified. The WNT10A gene has been confirmed as the second molecular candidate that has been identified and accounts for one-half of non-EDA patients and one-third of NSTA patients. Further studies using next generation sequencing (NGS) will help to identify other contributory genes in the remaining uncharacterized Spanish patients.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Displasia Ectodérmica/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Proteínas Wnt/genética , Adolescente , Adulto , Anodontia/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Éxons/genética , Feminino , Humanos , Lactente , Recém-Nascido , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Espanha , Adulto Jovem
11.
J Hum Genet ; 64(12): 1237-1242, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31591492

RESUMO

VAC14-related disorders include two distinct phenotypes, striatonigral degeneration [MIM# 617054] and Yunis-Varon syndrome. Striatonigral degeneration is a recently described childhood onset dystonia caused by pathogenic variants in VAC14. It is characterized by a period of apparent normalcy followed by abrupt onset neuroregression, dystonia, involuntary movements and degenerative brain lesions involving caudate nucleus, putamen and substantia nigra. Yunis-Varon syndrome is a well described severe condition characterised by skeletal findings and dysmorphism along with neuronal degeneration. Pathogenic variants in FIG4 have been previously reported to cause Yunis-Varon syndrome. Recently, loss of function variants in VAC14 were also reported in an individual affected with Yunis-Varon syndrome. Total seven individuals from four families are reported to have VAC14-related disorders till date. Here, we report another individual with clinical and radiological features suggestive of striatonigral degeneration with homozygous missense variant in VAC14. The patient fibroblasts showed extensive vacuolization, characteristic of VAC14-related disorders. We also review the phenotype and genotype associated with these disorders.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Degeneração Estriatonigral/genética , Displasia Cleidocraniana/genética , Displasia Ectodérmica/genética , Feminino , Genótipo , Homozigoto , Humanos , Lactente , Deformidades Congênitas dos Membros/genética , Micrognatismo/genética , Fenótipo
12.
Exp Dermatol ; 28(10): 1190-1195, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31585491

RESUMO

In P63-related ectodermal dysplasias (ED), the clinical characteristics focus on extra-cutaneous manifestations. The dermatological phenotype remains incompletely characterized. We report the dermatological features of 22 patients carrying a TP63 mutation. Erosions, erythroderma and pigmentary anomalies are characteristics of P63-related ED. Our data suggest that patients might be classified into two major P63-related disorders: AEC and EEC. RHS and ADULT represent mild AEC and EEC forms, respectively.


Assuntos
Displasia Ectodérmica/genética , Fatores de Transcrição/deficiência , Proteínas Supressoras de Tumor/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Fenda Labial/genética , Fissura Palatina/genética , Dermatite Esfoliativa/genética , Dermatoglifia , Displasia Ectodérmica/diagnóstico , Anormalidades do Olho/genética , Doenças Palpebrais/congênito , Doenças Palpebrais/genética , Feminino , Cabelo/anormalidades , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Mamilos/anormalidades , Transtornos da Pigmentação/genética , Policondrite Recidivante/genética , Avaliação de Sintomas , Anormalidades Dentárias/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Anormalidades Urogenitais/genética , Adulto Jovem
14.
Arch Argent Pediatr ; 117(5): 330-337, 2019 10 01.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31560489

RESUMO

INTRODUCTION: RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor. OBJECTIVE: To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017. RESULTS: Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases. CONCLUSION: The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 %), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.


Assuntos
Síndrome de Costello/diagnóstico , Displasia Ectodérmica/diagnóstico , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Argentina , Criança , Pré-Escolar , Síndrome de Costello/genética , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Adulto Jovem
15.
Shanghai Kou Qiang Yi Xue ; 28(3): 268-274, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31489414

RESUMO

PURPOSE: To identify the potentially pathogenic mutations in patients with ectodermal dysplasia (ED) and to investigate the pathogenicity of mutations by functional studies. METHODS: Eight Chinese ED patients were included in this study. Peripheral venous blood was taken from the patients and DNA was extracted. Whole-exome sequencing (WES) was performed using DNA samples. After quality control of the sequencing data, the potentially pathogenic mutations were screened. The pathogenicity of the mutations was predicted in silico. Immunofluorescence study and dual luciferase assays were performed to investigate the pathogenicity of the mutations. RESULTS: The effective rates of all sequencing samples were above 97.5% and the error rates were less than 0.03%. The proportions of Q20 were more than 97.0%. The average sequencing depths of the target region were more than 90×. The sequencing data were acceptable for further analysis. After data screening, three missense mutations of EDA were detected, including c.959A>G, c.1073A>G and c.1001G>A. The allele frequency was low in population database for all three mutations and in silico analysis indicated all three mutations were disease-causing. Immunofluorescence analysis showed that p65 protein nuclear translocation was compromised by EDA mutations, dual luciferase assays also showed that the activation of NF-κB pathway was decreased by EDA mutations. CONCLUSIONS: This study identified EDA mutations in Chinese ED patients and further verified the pathogenicity of the mutations by functional studies, contributing to the understanding of the pathogenesis of ED.


Assuntos
Displasia Ectodérmica , Mutação de Sentido Incorreto , Grupo com Ancestrais do Continente Asiático , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Humanos , Mutação , NF-kappa B
16.
BMC Genomics ; 20(1): 715, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533624

RESUMO

BACKGROUND: In mammals, hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that is characterized by sparse hair, tooth abnormalities, and defects in cutaneous glands. Only four genes, EDA, EDAR, EDARADD and WNT10A account for more than 90% of HED cases, and EDA, on chromosome X, is involved in 50% of the cases. In this study, we explored an isolated case of a female Holstein calf with symptoms similar to HED. RESULTS: Clinical examination confirmed the diagnosis. The affected female showed homogeneous hypotrichosis and oligodontia as previously observed in bovine EDAR homozygous and EDA hemizygous mutants. Under light microscopy, the hair follicles were thinner and located higher in the dermis of the frontal skin in the affected animal than in the control. Moreover, the affected animal showed a five-fold increase in the number of hair follicles and a four-fold decrease in the diameter of the pilary canals. Pedigree analysis revealed that the coefficient of inbreeding of the affected calf (4.58%) was not higher than the average population inbreeding coefficient (4.59%). This animal had ten ancestors in its paternal and maternal lineages. By estimating the number of affected cases that would be expected if any of these common ancestors carried a recessive mutation, we concluded that, if they existed, other cases of HED should have been reported in France, which is not the case. Therefore, we assumed that the causal mutation was dominant and de novo. By analyzing whole-genome sequencing data, we identified a large chromosomal inversion with breakpoints located in the first introns of the EDA and XIST genes. Genotyping by PCR-electrophoresis the case and its parents allowed us to demonstrate the de novo origin of this inversion. Finally, using various sources of information we present a body of evidence that supports the hypothesis that this mutation is responsible for a skewed inactivation of X, and that only the normal X can be inactivated. CONCLUSIONS: In this article, we report a unique case of X-linked HED affected Holstein female calf with an assumed full inactivation of the normal X-chromosome, thus leading to a severe phenotype similar to that of hemizygous males.


Assuntos
Inversão Cromossômica/genética , Cromossomos de Mamíferos/genética , Displasia Ectodérmica/genética , Ectodisplasinas/genética , Heterozigoto , RNA Longo não Codificante/genética , Animais , Bovinos , Feminino , Masculino , Linhagem , Sequenciamento Completo do Genoma
17.
Am J Med Genet A ; 179(11): 2246-2251, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31368252

RESUMO

Adams-Oliver syndrome (AOS) is a rare congenital disease characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It shows significant genetic heterogeneity and can be transmitted by autosomal dominant or recessive inheritance. Recessive inheritance is associated with mutations of DOCK6 or EOGT; however, only few cases have been published so far. We present two families with EOGT-associated AOS. Due to pseudodominance in one family, the recognition of the recessive inheritance pattern was difficult. We identified two novel AOS-causing mutations (c.404G>A/p.Cys135Tyr and c.311+1G>T). The phenotype in the presented families was dominated by large ACC, whereas TTLD were mostly subtle or even absent and no major malformations occured. Our observations along with the previously published cases indicate that the two types of recessive AOS (EOGT- vs. DOCK6-associated) differ significanty regarding the frequency of neurologic or ocular deficits.


Assuntos
Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Mutação , N-Acetilglucosaminiltransferases/genética , Dermatoses do Couro Cabeludo/congênito , Criança , Consanguinidade , Éxons , Estudos de Associação Genética/métodos , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/genética
19.
Proc Natl Acad Sci U S A ; 116(35): 17361-17370, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31413199

RESUMO

Mutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism is however not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations. Transcriptome analyses revealed stepwise cell fate transitions during epidermal commitment: Specification from multipotent simple epithelium to basal stratified epithelia and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by p63 mutations occurred during the specification switch from the simple epithelium to the basal-stratified epithelial fate. Single-cell transcriptome and pseudotime analyses of cell states identified mesodermal activation that was associated with the deviated commitment route of EEC iPSCs. Integrated analyses of differentially regulated genes and p63-dependent dynamic genomic enhancers during epidermal commitment suggest that p63 directly controls epidermal gene activation at the specification switch and has an indirect effect on mesodermal gene repression. Importantly, inhibitors of mesodermal induction enhanced epidermal commitment of EEC iPSCs. Our findings demonstrate that p63 is required for specification of stratified epithelia, and that epidermal commitment defects caused by p63 mutations can be reversed by repressing mesodermal induction. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Epitélio/metabolismo , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Epiderme/embriologia , Epiderme/metabolismo , Epitélio/embriologia , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Células-Tronco Pluripotentes Induzidas/metabolismo , Queratinócitos/metabolismo , Mutação , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
20.
Rev. medica electron ; 41(4): 1035-1041, jul.-ago. 2019.
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1094108

RESUMO

RESUMEN Las displasias ectodérmicas constituyen alteraciones de los derivados embriológicos del ectodermo. Paciente adulta, con hipoparatiroidismo, llamó la atención por su fenotipo y fue remitida de la consulta de Neurología a la consulta Genética. Se diagnosticó una displasia ectodérmica hipohidrótica, de origen genético con herencia autosómica dominante, poco común para esta entidad. Se presenta este caso con el objetivo de describir las manifestaciones clínicas de esta alteración genética, las cuales nunca fueron objeto de interés médico resultando inadvertidas para su estudio y diagnóstico. Esta alteración se asocia a una condición patológica como el hipoparatiroidismo, en la literatura revisada no se encontraron reportes de la misma. La evaluación clínica de la paciente permitió hacer el diagnóstico y explicar muchos de los problemas para los cuales no existían respuestas, así como ofrecer un asesoramiento genético adecuado para ella y para sus familiares con riesgo de padecer una condición genética similar.


ABSTRACT Ectodermic dysplasias are alterations of the ectoderm embryologic derivatives. This is a case of an adult female patient with hypoparathyroidism, drawing attention due to her phenotype; she was remitted by the consultation of Neurology to the Genetic one. She was diagnosed a hypohidrotic ectodermal dysplasia, of genetic origin with autosomal dominant inheritance, what is very rare for this entity. The case is presented with the aim of describing the clinical manifestation of this genetic alteration that never drew medical interest and nobody diagnosed or studied. It is associated to a pathologic condition like hypothyroidism and was not reported in medical literature before. The clinical evaluation of the patient allowed arriving to the diagnostic and explaining many problems that were unexplained, and also offering the adequate genetic advice to her and her relatives likewise at risk of suffering a similar genetic condition.


Assuntos
Humanos , Feminino , Adulto , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/etiologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/tratamento farmacológico , Displasia Ectodérmica/epidemiologia , Aconselhamento Genético , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/etiologia , Qualidade de Vida , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/etiologia
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