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1.
Nature ; 574(7777): 249-253, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578523

RESUMO

The integrity of the mammalian epidermis depends on a balance of proliferation and differentiation in the resident population of stem cells1. The kinase RIPK4 and the transcription factor IRF6 are mutated in severe developmental syndromes in humans, and mice lacking these genes display epidermal hyperproliferation and soft-tissue fusions that result in neonatal lethality2-5. Our understanding of how these genes control epidermal differentiation is incomplete. Here we show that the role of RIPK4 in mouse development requires its kinase activity; that RIPK4 and IRF6 expressed in the epidermis regulate the same biological processes; and that the phosphorylation of IRF6 at Ser413 and Ser424 primes IRF6 for activation. Using RNA sequencing (RNA-seq), histone chromatin immunoprecipitation followed by sequencing (ChIP-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of skin in wild-type and IRF6-deficient mouse embryos, we define the transcriptional programs that are regulated by IRF6 during epidermal differentiation. IRF6 was enriched at bivalent promoters, and IRF6 deficiency caused defective expression of genes that are involved in the metabolism of lipids and the formation of tight junctions. Accordingly, the lipid composition of the stratum corneum of Irf6-/- skin was abnormal, culminating in a severe defect in the function of the epidermal barrier. Collectively, our results explain how RIPK4 and IRF6 function to ensure the integrity of the epidermis and provide mechanistic insights into why developmental syndromes that are characterized by orofacial, skin and genital abnormalities result when this axis goes awry.


Assuntos
Diferenciação Celular , Células Epidérmicas/citologia , Epiderme/fisiologia , Fatores Reguladores de Interferon/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Anormalidades Múltiplas/genética , Animais , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Células Epidérmicas/metabolismo , Epiderme/embriologia , Anormalidades do Olho/genética , Feminino , Dedos/anormalidades , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Joelho/anormalidades , Articulação do Joelho/anormalidades , Lábio/anormalidades , Metabolismo dos Lipídeos/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Proteínas Serina-Treonina Quinases/genética , Sindactilia/genética , Anormalidades Urogenitais/genética
2.
Medicine (Baltimore) ; 98(39): e17342, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574874

RESUMO

RATIONALE: The karyotype 49,XXXXY is a rare form of Klinefelter syndrome usually presenting with ambiguous genitalia, facial dysmorphism, mental retardation, and a combination of cardiac, skeletal, and other malformations. PATIENT CONCERNS: We describe a 19-year-old man, whose chromosomal analysis of peripheral blood revealed a karyotype of 49,XXXXY. His mental development and motor ability were significantly delayed. At the age of 19, he had failed to develop secondary sexual characteristics. His random blood glucose level was 19.61 mmol/L, and he showed dry mouth, polydipsia, and polyuria. He had a characteristic facial appearance with prognathism, widened nasal bridge, and strabismus. His bilateral elbow rotation was limited. He had atrophic testes with micropenis. Ophthalmic examination revealed a polar cataract in both eyes. DIAGNOSIS: He was diagnosed with Klinefelter syndrome associated with cleft palate, hypothyroidism, cataracts, diabetes, and other anomalies. INTERVENTIONS: After the initial diagnosis, the patient received intensive insulin therapy to correct hyperglycemia, and he received calcium and vitamin D supplements. The patient also received testosterone and thyroid hormone replacement therapy for primary hypogonadism. OUTCOMES: The patient was discharged 12 days after receiving treatment; meanwhile, there were no clinical symptoms of dry mouth, polyuria and polyuria, and his blood glucose level was controlled. LESSONS: The combination of cleft palate, hypothyroidism, cataracts, diabetes, and osteoporosis in 49,XXXXY syndrome has not yet been reported. Early treatment and appropriate care can significantly improve the patient's quality of life and prevent serious consequences.


Assuntos
Catarata/congênito , Fissura Palatina/genética , Hipotireoidismo Congênito/genética , Diabetes Mellitus/congênito , Transtornos dos Cromossomos Sexuais/complicações , Anormalidades Múltiplas/genética , Aneuploidia , Cromossomos Humanos X/genética , Humanos , Cariotipagem , Masculino , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/genética , Adulto Jovem
3.
J Appl Oral Sci ; 27: e20180649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596367

RESUMO

OBJECTIVE: Cleft palate (CP) is a congenital birth defect caused by the failure of palatal fusion. Little is known about the potential role of DNA methylation in the pathogenesis of CP. This study aimed to explore the potential role of DNA methylation in the mechanism of CP. METHODOLOGY: We established an all-trans retinoic acid (ATRA)-induced CP model in C57BL/6J mice and used methylation-dependent restriction enzymes (MethylRAD, FspEI) combined with high-throughput sequencing (HiSeq X Ten) to compare genome-wide DNA methylation profiles of embryonic mouse palatal tissues, between embryos from ATRA-treated vs. untreated mice, at embryonic gestation day 14.5 (E14.5) (n=3 per group). To confirm differentially methylated levels of susceptible genes, real-time quantitative PCR (qPCR) was used to correlate expression of differentially methylated genes related to CP. RESULTS: We identified 196 differentially methylated genes, including 17,298 differentially methylated CCGG sites between ATRA-treated vs. untreated embryonic mouse palatal tissues (P<0.05, log2FC>1). The CP-related genes Fgf16 (P=0.008, log2FC=1.13) and Tbx22 (P=0.011, log2FC=1.64,) were hypermethylated. Analysis of Fgf16 and Tbx22, using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), identified 3 GO terms and 1 KEGG pathway functionally related to palatal fusion. The qPCR showed that changes in expression level negatively correlated with methylation levels. CONCLUSIONS: Taken together, these results suggest that hypermethylation of Fgf16 and Tbx22 is associated with decreased gene expression, which might be responsible for developmental failure of palatal fusion, eventually resulting in the formation of CP.


Assuntos
Fissura Palatina/genética , Metilação de DNA , Fatores de Crescimento de Fibroblastos/genética , Expressão Gênica , Proteínas com Domínio T/genética , Animais , Fissura Palatina/embriologia , Fissura Palatina/patologia , Feminino , Fatores de Crescimento de Fibroblastos/análise , Masculino , Camundongos Endogâmicos C57BL , Domínios e Motivos de Interação entre Proteínas , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Análise de Sequência de DNA , Proteínas com Domínio T/análise
4.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(9): 1174-1180, 2019 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-31512462

RESUMO

Objective: To investigate the correlation between down-regulation of miR-381-3p and inhibition of osteogenic differentiation of mouse embryonic palatal mesenchymal (MEPM) cells in 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cleft palate of fetal mice. Methods: Thirty-two pregnant mice were randomly divided into TCDD group and control group, 16 in each group. On embryonic day 10.5 (E10.5), the pregnant mice in TCDD group were orally administrated with TCDD at dosage of 28 µg/kg, while the pregnant mice in control group received equivalent corn oil. The pregnant mice in each group were sacrificed on E13.5 and E14.5, fetal palates were collected for analysis. The expression of miR-381-3p was detected by real-time fluorescent quantitative PCR and the protein expressions of runt- related transcription factor 2 (RUNX2) and osteopontin (OPN) were detected by Western blot. MEPM cells were extracted from fetal palates on E14.5 in control group and passaged. The 3rd passage cells were cultured with TCDD at dosage of 10 nmol/L for 0, 0.5, 1, 2, and 3 days. The expression of miR-381-3p was detected after 0, 0.5, 1, 2, and 3 days and the protein expressions of RUNX2 and OPN were detected after 0, 1, 2, and 3 days. Then, the 3rd passage cells were divided into 4 groups. The MEPM cells were transfected with miR-381-3p inhibitor (inhibitor group), NC inhibitor (NC inhibitor group) and miR-381-3p mimics (mimics group), NC mimics (NC mimics group) for 48 hours, respectively. And the expressions of miR-381-3p and the protein expressions of RUNX2 and OPN were detected. Results: On E13.5 and E14.5, 96 fetal mice in control group and 92 in TCDD group were obtained. The bilateral palates contacted in control group on E14.5, and a gap between the bilateral palates existed in TCDD group. On E13.5 and E14.5, the relative expressions of miR-381-3p and RUNX2 and OPN proteins were significant lower in TCDD group than in control group ( P<0.05). The relative expression of miR-381-3p at 0.5 and 1 day after TCDD treatment of MEPM cells were significantly lower than that at 0 day ( P<0.05); then, the relative expressions at 2 and 3 days significantly increased, showing no significant difference when compared with that at 0 day ( P>0.05). The relative expressions of RUNX2 and OPN proteins at 1, 2, and 3 days were significantly lower than that at 0 day ( P<0.05). The relative expressions of miR-381-3p and RUNX2 and OPN proteins significantly lower in inhibitor group than in NC inhibitor group ( P<0.05) and higher in mimics group than in NC mimics group ( P<0.05). Conclusion: Down-regulation of miR-381-3p expression may be associated with inhibition of osteogenic differentiation of MEPM cells in TCDD-induced cleft palate of fetal mice.


Assuntos
Fissura Palatina , Regulação para Baixo , MicroRNAs , Dibenzodioxinas Policloradas , Animais , Fissura Palatina/induzido quimicamente , Fissura Palatina/embriologia , Fissura Palatina/genética , Fissura Palatina/fisiopatologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Osteogênese/genética , Palato/fisiopatologia , Gravidez
5.
J Biol Regul Homeost Agents ; 33(3 Suppl. 1): 145-151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31538461

RESUMO

Nonsyndromic cleft lip with or without cleft palate is the most common craniofacial anomaly affecting around 1 in 700 live births worldwide. Clefts of the human face can be classified anatomically as cleft palate only (CPO), cleft lip only (CLO), cleft lip and palate (CLP) or a combined group of cleft lip with or without cleft palate (CL/P), based on different in embryologic development. These malformations have some genetic origin, in fact several association studies have been performed to obtain important information about the candidate genes; but more important are gene-environment interactions that play an increasing role in its etiology. Epidemiological studies have shown how environmental factors (alcohol, smoking, drugs), as well as possible gene-environment interactions, play an important role in the onset of the malformation. On the contrary, folic acid intake seems to have a protective effect. In this review, we analyze the role of environmental factors related to onset of cleft.


Assuntos
Fenda Labial/etiologia , Fissura Palatina/etiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Fenda Labial/genética , Fissura Palatina/genética , Ácido Fólico/administração & dosagem , Interação Gene-Ambiente , Humanos , Fumar/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/complicações
6.
J Craniofac Surg ; 30(5): e465-e467, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31299817

RESUMO

Van der Woude syndrome (VWS) is a rare autosomal dominant disease, first reported in the literature in 1845 by Demarquay and subsequently thoroughly described in 1954 by Van der Woude. Van der Woude Syndrome is the most common form of syndromic orofacial clefting and individuals with this syndrome account for 2% of all cleft cases. Van der Woude syndrome clinically presents with congenital lip pits. These lip pits occur on paramedian portion of the vermillion border of the lip. In VWS, congenital lip pits occur in concurrence with cleft lip and/or cleft palate and represent the most common clinical problem occurring in 80% of the patients. Lip pits result due to notching of the lips at an early stage of development with fixation of tissues at the base of the notch or they may result from a failure of complete union of embryonic lateral sulci of lip. Single lip sinuses without any cleft syndrome are rare; lower lip fistulas in VWS are generally asymptomatic, and surgical management is usually accomplished because of aesthetic concerns. However, in some cases, patients may complain of watery drainage or hypotonia of the lower lip. Herein, the authors report a novel frameshift mutation in IRF6 gene which may contribute to better understanding the genetic aspect of VWS.


Assuntos
Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Fatores Reguladores de Interferon/genética , Lábio/anormalidades , Mutação , Pré-Escolar , Humanos , Masculino
7.
Medicine (Baltimore) ; 98(26): e16170, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261547

RESUMO

OBJECTIVE: Non-syndromic cleft of the lip and/or palate (NSCL/P) is one of the most common polygenic diseases. In this study, both case-control and family-based association study were used to confirm whether the Single Nucleotide Polymorphisms (SNPs) were associated with NSCL/P. METHODS: A total of 37 nuclear families and 189 controls were recruited, whose blood DNA was extracted and subjected to genotyping of SNPs of 27 candidate genes by polymerase chain reaction-improved multiple ligase detection reaction technology (PCR-iMLDR). Case-control statistical analysis was performed using the SPSS 19.0. Haplotype Relative Risk (HRR), transmission disequilibrium test (TDT), and Family-Based Association Test (FBAT) were used to test for over-transmission of the target alleles in case-parent trios. The gene-gene interactions on NSCL/P were analyzed by Unphased-3.1.4. RESULTS: In case-control statistical analysis, only C14orf49 chr14_95932477 had statistically significant on genotype model (P = .03) and allele model (P = .03). Seven SNPs had statistically significant on TDT. None of 26 alleles has association with NSCL/P on FBAT. Some SNPs had haplotype-haplotype interactions and genotype-genotype interactions. CONCLUSION: C14orf49 chr14_95932477 was significantly different between cases and controls on genotype model and allele model by case-control design. Seven SNPs were significantly different on HRR. Four SNPs were significantly different on TDT.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Fenda Labial/complicações , Fissura Palatina/complicações , Família , Feminino , Estudos de Associação Genética , Humanos , Masculino , Modelos Genéticos , Fosfatases de Fosfoinositídeos/genética , Proteínas de Transporte Vesicular/genética
8.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(6): 670-675, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31238617

RESUMO

Objective: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with its genetic evidence widely explored. This study explored the potential the parent-of-origin (PoO) effect of WNT pathway on the risks of NSCL/P, using a case-parent trio design. Methods: Data on the single nucleotide polymorphism (SNP) of WNT genes were selected from a genome-wide association study (GWAS). A total of 806 Chinese non-syndromic cleft lip patients, with or without cleft palate (NSCL/P) case-parent trios, were gathered from an international consortium. PoO effect of WNT pathway genes and its haplotypes were explored by log-linear models. Additional Wald tests were performed to assess: a) the heterogeneity of PoO effect between different maternal exposures, b) the interaction between PoO effect, c) maternal exposure to environmental tobacco smoke (ETS), and d) multivitamin supplementation during pregnancy. The threshold for statistical significance was adjusted as 3.47×10(-4), according to Bonferroni correction. Results: After quality control, a total of 144 SNPs within seven genes were included for analyses, among which 8 SNPs were of potential PoO effect (P<0.05). However, none of them achieved the statistical significance after Bonferroni correction. The haplotype rs4074668-rs12725747 (T-A) on WNT9A showed significant PoO effect, based on the haplotype test for PoO (P=2.74×10(-4)). In addition, no statistically significant interaction was found in further exploration of this haplotype under environmental exposures as ETS or multivitamin supplementation. Conclusions: Genes in the WNT pathway may influence the NSCL/P risks through the potential PoO effect. Particularly, the haplotype rs4074668-rs12725747 (T-A) on WNT9A presented significant PoO effect on NSCL/P, statistically. From this current study, findings on WNT pathway related risks among the NSCL/P, need to be further validated by independent samples in the future.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Via de Sinalização Wnt/genética , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez
9.
Int J Pediatr Otorhinolaryngol ; 124: 54-58, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158572

RESUMO

BACKGROUND: Submucous cleft palate is a cleft of the secondary palate with low phenotypic gene expression. It can occur as an isolated malformation or associated with a syndrome that includes certain facial features and other vocal tract malformations. Velopharyngeal insufficiency (VPI) is rare in cases of non - syndromic occult clefts of the secondary palate (OSCSP). In contrast, syndromic OCSP has a high prevalence of VPI. VPI requires surgical treatment in the vast majority of cases. OBJECTIVE: To present a case of OSCSP with VPI after partial tonsillectomy and adenoidectomy (T & A) associated with facial features and other vocal tract malformations. A chromosomal abnormality (8q22.2 deletion) was demonstrated by cytogenetic testing. CASE PRESENTATION: Eight year old female with VPI following partial T & A. OSCSP was diagnosed. Complete T & A was performed in preparation for a pharyngeal flap. Pharyngeal flap surgery was customized according to findings of videonasopharyngoscopy (VNP) and multiplanar videofluoroscopy (MPVF). VPI was corrected without intraoperative or postoperative complications. CONCLUSION: The presence of multiple vocal tract malformations should be a red flag for suspecting a syndromic OSCSP. Surgical treatment of VPI in cases of OSCSP should be performed after complete T & A, Imaging procedures for assessing neck blood vessels and it should be customized according to imaging (VNP and MPVF) findings.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 8 , Fissura Palatina/genética , Insuficiência Velofaríngea/genética , Insuficiência Velofaríngea/cirurgia , Criança , Fissura Palatina/complicações , Feminino , Humanos , Insuficiência Velofaríngea/complicações
10.
Genet Epidemiol ; 43(6): 704-716, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31172578

RESUMO

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.


Assuntos
Encéfalo/anormalidades , Fenda Labial/classificação , Fenda Labial/genética , Fissura Palatina/classificação , Fissura Palatina/genética , Loci Gênicos , Marcadores Genéticos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Encéfalo/patologia , Fenda Labial/patologia , Fissura Palatina/patologia , Humanos , Transcriptoma
11.
An Acad Bras Cienc ; 91(2): e20180945, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31241704

RESUMO

DNA methylation is essential for spatiotemporally-regulated gene expression in embryonic development. TBX22 (Chr X: 107667964-107688978) functioning as a transcriptional repressor affects DNA binding, sumoylation, and transcriptional repression associated with X-linked cleft palate. This study aimed to explore the relationship and potential mechanism between TBX22 exon 5 methylation and palatal shelf fusion induced by all-trans retinoic acid (ATRA). We performed DNA methylation profiling, using MethylRAD-seq, after high throughput sequencing of mouse embryos from control (n=9) and ATRA-treated (to induce cleft palate, n=9) C57BL/6J mice at embryonic gestation days(E) 13.5, 14.5 and 16.5. TBX22 exon 5 was hyper-methylated at the CpG site at E13.5 (P=0.025, log2FC=1.5) and E14.5 (P=0.011, log2FC:1.5) in ATRA-treated, whereas methylation TBX22 exon 5 at the CpG site was not significantly different at E16.5 (P=0.808, log2FC=-0.2) between control and ATRA-treated. MSP results showed a similar trend consistent with the MethylRAD-seq results. qPCR showed the change in TBX22 exon 5 expression level negatively correlated with its TBX22 exon 5 methylation level. These results indicate that changes in TBX22 exon 5 methylation might play an important regulatory role during palatal shelf fusion, and may enlighten the development of novel epigenetic biomarkers in the treatment of CP in the future.


Assuntos
Fissura Palatina/embriologia , Desenvolvimento Embrionário/genética , Éxons/genética , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Proteínas com Domínio T/genética , Animais , Fissura Palatina/genética , Modelos Animais de Doenças , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Gravidez
12.
J Clin Pediatr Dent ; 43(4): 288-291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31094634

RESUMO

The 13q deletion syndrome is a rare genetic disorder caused by structural and functional monosomy of chromosome 13. On 13q34, which is the terminal of the long arm, causative genes of coagulation factors VII and X (FVII and FX) are mapped. Patients with a combination of FVII and FX deficiencies are extremely rare and there have been few articles about perioperative coagulation support for such patients. Herein, we report on a case of bilateral cleft lip and palate accompanied by 13q deletion syndrome with deficiencies of FVII and FX. The chromosomal investigation indicated 46, XX, del(13)(q33) by G-banding. Prothrombin time and activated partial thromboplastin time were found to be 21.0 seconds (sec) (prothrombin time-international normalized ratio 1.76) and 41.6 sec (normal range; 23.9 - 39.7 sec), respectively. The activities of coagulation FVII and FX were 22% and 36%, respectively. A two-stage cheiloplasty was performed at 4 and 7 months of age followed by a palatoplasty at 1 year and 6 months. Tranexamic acid was given intravenously three times a day for three days after each surgery. There were no adverse events such as bleeding from the oral or nasal cavities and healing of the surgical wound was good without dehiscence.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 13 , Fenda Labial , Fissura Palatina , Deficiência do Fator VII , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13/genética , Fenda Labial/genética , Fissura Palatina/genética , Fator VII , Deficiência do Fator VII/genética , Humanos , Palato
13.
Mol Med Rep ; 20(1): 513-528, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115538

RESUMO

Non­syndromic orofacial clefts (NSOC), which include cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), are common congenital birth defects in humans. Accumulating evidence indicates that long non­coding RNAs (lncRNAs) and microRNAs (miRNAs or miRs) play important roles in NSOC; however, the potential regulatory associations between them remain largely unknown. In this study, we performed next­generation RNA sequencing (RNA­seq) to identify transcriptome profiles, including mRNAs, lncRNAs and miRNAs, in patients with CL/P and CPO. A total of 36 lncRNAs, 1,341 mRNAs and 60 miRNAs were found to be differentially expressed in the CL/P group compared to the control group, and 57 lncRNAs, 1,255 mRNAs and 162 miRNAs were found to be differentially expressed in the CPO group compared to the control group. Subsequently, reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was performed to validate the expression of selected lncRNAs, miRNAs and mRNAs. In addition, bioinformatics methods were employed to explore the potential functions of ncRNAs and to construct lncRNA­miRNA­mRNA regulatory networks. To the best of our knowledge, this is the first study to comprehensively analyze regulated non­coding RNAs (ncRNAs) in CL/P and CPO, providing a novel perspective on the etiology of NSOC and laying the foundation for future research into the potential regulatory mechanisms of ncRNAs and mRNAs in NSOC.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Encéfalo/patologia , Pré-Escolar , Fenda Labial/sangue , Fenda Labial/patologia , Fissura Palatina/sangue , Fissura Palatina/patologia , Biologia Computacional , Feminino , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , MicroRNAs/sangue , RNA Longo não Codificante/sangue , RNA Mensageiro/sangue , RNA Mensageiro/genética , Transcriptoma/genética
14.
Shanghai Kou Qiang Yi Xue ; 28(1): 57-62, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31081001

RESUMO

PURPOSE: To study DNA methylation patterns of non-syndromic cleft lip/palate(NSCL/P) using bioinformatic methods, including methylated positions and regions. METHODS: Whole blood DNA methylation data of NSCL/P samples was download from Gene Expression Omnibus(GEO) database, including 67 NSCL/P cases and 59 controls without birth defects. Data analysis included ①data cleaning, such as probes filtering, quality control and normalization; ②differential methylation analysis, including methylated positions and regions; ③Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on differential methylated genes. R 3.4.3 software was used for data cleaning, differential methylated positions and regions analysis. DAVID6.8 tool was used for GO and KEGG analysis. RESULTS: 814 differential methylated positions were detected (adjusted P<0.001,|Δß|>0.125), of which 178 were hypermethylated in NSCL/P patients, and 636 were hypomethylated. In addition, 386 differential methylated regions were identified (P<0.05), of which 204 were hypermethylation regions and 182 were hypomethylation regions. GO analysis showed that 38 differential methylated genes were involved in 7 kinds of biological processes, 163 differential methylated genes were involved in 3 kinds of molecular functions, and 114 differential methylated genes were involved in 3 kinds of cellular components (P<0.01). KEGG analysis showed that 59 differential methylated genes were involved in 9 kinds of signal pathways. CONCLUSIONS: Abnormal DNA methylation patterns of NSCL/P might be an important epigenetic mechanism affecting the development of NSCL/P. This study might contribute to the identification of identification of biomarkers and targeted interventions of NSCL/P.


Assuntos
Fenda Labial , Fissura Palatina , Metilação de DNA , Fenda Labial/genética , Fissura Palatina/genética , Biologia Computacional , Humanos , Palato , Software
15.
BMC Genomics ; 20(1): 349, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068123

RESUMO

BACKGROUND: Palatoschisis or cleft palate is a known anomaly in pigs resulting in their death. However, little is known about its aetiology. A detailed description of the phenotype was derived from necropsy and by computed tomography revealing that all 20 cases also exhibited hypodontia and renal cysts. Furthermore, a genetic origin was assumed due to dominant inheritance as all 20 recorded cases were confirmed offspring of a single boar. RESULTS: Single nucleotide variant (SNV) genotyping data were used to map the defect in the porcine genome and led to the detection of a chromosomal imbalance in the affected offspring. Whole genome sequencing of an affected piglet and a normal full sib was used to identify a chromosomal translocation and to fine map the breakpoints in the genome. Finally, we proved that the boar, which sired the malformed piglets, carried a balanced translocation. The detected translocation of Mb-sized segments of chromosome 8 and 14 had not been previously observed during karyotyping. All affected offspring were shown to be carriers of a partial trisomy of chromosome 14 including the FGFR2 gene, which is associated with various dominant inherited craniofacial dysostosis syndromes in man, and partial monosomy of chromosome 8 containing MSX1 known to be associated with tooth agenesis and orofacial clefts in other species. CONCLUSIONS: This study illustrates the usefulness of recently established genomic resources in pigs. In this study, the application of genome-wide genotyping and sequencing methods allowed the identification of the responsible boar and the genetic cause of the observed defect. By implementing systematic surveillance, it is possible to identify genetic defects at an early stage and avoid further distribution of congenital disorders.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Fissura Palatina/genética , Polimorfismo de Nucleotídeo Único , Suínos/genética , Anormalidades Múltiplas/patologia , Animais , Fissura Palatina/patologia , Feminino , Masculino , Síndrome , Sequenciamento Completo do Genoma
16.
Mol Med Rep ; 19(5): 3831-3840, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896870

RESUMO

Congenital heart disease (CHD), and cleft lip and palate (CLP) are currently the most common types of structural malformation in infants. Various methods have been used to identify the disease­associated genes. However, targeted next­generation sequencing (NGS) is not yet considered an option for routine use. Thus, the present study aimed to assess the safety and feasibility of using targeted NGS in patients with CHD concomitant with CLP. Between November 2015 and May 2017, a total of 17 patients with CHD concomitant with CLP, who were excluded from a diagnosis of trisomy syndrome, were selected at The Second Xiangya Hospital of Central South University (Changsha, China). Genomic DNA was extracted from peripheral blood samples of the patients. The copy number variants (CNVs) were determined by conducting a single nucleotide polymorphism (SNP) array with Illumina HumanOmni1­Quad Beadchip, while information on other gene mutations was obtained from targeted sequencing. The functions of gene mutations were then predicted using the PolyPhen­2, SIFT and Mutation Taster tools. Finally, Sanger sequencing was used to verify the mutations. The results identified no pathogenic mutations in CNVs analyzed by high­throughput SNP sequencing. Targeted NGS results demonstrated that 10 patients (58.8%) carried gene mutations, including 4 (23.5%) genetically diagnosed cases and 6 (35.3%) cases with unknown etiology. The 4 known diseases were Opitz G/BBB syndrome caused by MID1 gene mutation, Loeys­Dietz syndrome caused by TGFBR1 gene mutation, Ritscher­Schinzel/3C syndrome caused by KIAA0196 gene mutation and CHARGE syndrome caused by CHD7 gene mutation. The remaining 6 cases were not genetically diagnosed, although they carried candidate genes. In conclusion, the present study demonstrated that targeted NGS was an effective and accurate candidate gene detection method in patients with CHD concomitant with CLP.


Assuntos
Biomarcadores/sangue , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Cardiopatias Congênitas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Criança , Pré-Escolar , Fenda Labial/sangue , Fenda Labial/complicações , Fenda Labial/genética , Fissura Palatina/sangue , Fissura Palatina/complicações , Fissura Palatina/genética , Feminino , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Humanos , Lactente , Masculino
17.
Rev. bras. cir. plást ; 34(1): 94-100, jan.-mar. 2019. ilus, tab
Artigo em Inglês, Português | LILACS | ID: biblio-994554

RESUMO

Introdução: As fissuras labiopalatinas são as malformações congênitas mais comuns dentre as que ocorrem na cabeça e pescoço, e se devem à falha de fusão dos processos faciais embrionários durante as primeiras 12 semanas de gestação. Sua apresentação fenotípica é variada e com diferentes níveis de complexidade. O objetivo é determinar o perfil epidemiológico dos pacientes portadores de fissuras labiopalatinas atendidos no Hospital Regional da Asa Norte (HRAN) quanto a sexo, tipo de fissura, lateralidade, idade, presença de síndromes associadas e procedimentos cirúrgicos corretivos. Métodos: Trata-se de um estudo descritivo retrospectivo no qual foram analisados 322 prontuários de pacientes atendidos pela equipe do HRAN no período de agosto de 2013 a julho de 2017. Os dados colhidos foram lançados em planilha Excel e submetidos à análise estatística. O trabalho foi aprovado pelo Comitê de Ética e Pesquisa. Resultados: Dos 322 pacientes atendidos no serviço, 169 eram do sexo masculino (52,48%). O tipo de fissura mais frequente foi a transforâmica (65,25%). Com relação à lateralidade, observou-se maior predomínio da fissura à esquerda (20,50%). Apenas 19% dos pacientes possuem malformações associadas. A queiloplastia foi a correção cirúrgica mais realizada pelo serviço (54%). A idade dos pacientes variou de 1 ano até 53 anos, com mediana de 1,87 anos. Conclusão: O estudo contribuiu com informações importantes para a sociedade, governo e profissionais envolvidos no tratamento. Em consonância com a literatura, observou-se que a fissura mais prevalente foi a transforâmica unilateral esquerda e a cirurgia mais realizada foi a queiloplastia.


Introduction: Cleft lip and palate, the most common congenital malformations of the head and neck, result from fusion failure of embryonic facial processes during the first 12 weeks of pregnancy. Their phenotypic presentation varies and involves different levels of complexity. The objective is to determine the epidemiological profile of patients with cleft lip and palate treated at the Hospital Regional da Asa Norte regarding sex, cleft type, laterality, age, presence of associated syndromes, and corrective surgical procedures. Methods: This was a retrospective descriptive study of 322 medical records of patients treated by the HRAN team from August 2013 to July 2017. The data collected were entered into an Excel spreadsheet and submitted to statistical analysis. The study received ethical approval. Results: Of the 322 patients enrolled in the service, 169 were male (52.48%). The most frequent type of cleft was the trans-foramen (65.25%). With regard to laterality, a higher prevalence of cleft was observed on the left (20.50%). Only 19% of the patients had associated malformations. Cheiloplasty was the most frequent surgical correction performed by service (54%). The age of the patients was 1­53 years (median, 1.87 years). Conclusion: The study contributes information important to society, government, and treatment professionals. In line with the literature, the more prevalent cleft was unilateral left trans-foramen and the most frequent surgery was cheiloplasty.


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Pacientes/estatística & dados numéricos , Anormalidades Congênitas , Fissuras Dentárias/congênito , Fenda Labial , Fissura Palatina/cirurgia , Fissura Palatina/complicações , Fissura Palatina/genética , Procedimentos Cirúrgicos Reconstrutivos/métodos
18.
Clin Epigenetics ; 11(1): 40, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832715

RESUMO

BACKGROUND: Isolated orofacial clefts are among the most common congenital birth defects. Although the underlying biological mechanisms remain largely unknown, clefts are thought to be complex disorders influenced by genetic, environmental, and potentially epigenetic factors. METHODS: In blood samples from 2- to 3-day-old infants (n = 747) collected in a nationwide population-based study of orofacial clefts in Norway, we measured DNA methylation profiles for more than 450,000 CpGs and then conducted epigenome-wide association analyses (EWAS). We tested methylation profile difference at each CpG between controls (n = 436) and each of the cleft subtypes (92 cleft lip only, CLO; 84 cleft palate only, CPO; 132 cleft lip and palate, CLP). We also compared controls to various combinations of case groups and compared case subtypes to each other. Finally, using the EWAS results, we searched for larger differentially methylated regions (DMRs) associated with orofacial clefts. RESULTS: In EWAS comparing controls to individual cleft subtypes, we found no significant associations at a Bonferroni P value threshold of 10-7. After pooling case groups, we found two significantly differentially methylated CpGs: cg09696939 near gene BICC1 is associated with CLO+CLP (P = 9.58 × 10-8); cg26985354 in gene CLASRP is associated with CPO+CLP (P = 7.38 × 10-8). In DMR analysis, we identified a total of 56 significant regions when comparing controls to individual cleft subtypes (10 for CLO, 6 for CPO, 41 for CLP). Only one DMR is shared among the three cleft groups. In combined case group analysis, we found 26 DMRs for CLP+CLO, 31 for CLP+CPO, and 37 when all subtypes are combined. Finally, in case-case comparisons of subtypes, we identified 10 DMRs when comparing CLP to CPO, 9 in CLP compared to CLO, and 13 in CLP compared to CPO. CONCLUSIONS: We identified two individual CpGs and multiple DMRs that differ between controls and cleft case subtypes. Although we find some evidence for the possible role of DNA methylation in etiology of orofacial clefts, our study does not support previous reports of widespread differences in blood DNA methylation between babies with and without facial clefts.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Proteínas de Ligação a RNA/genética , Fatores de Processamento de Serina-Arginina/genética , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Masculino , Noruega
19.
Mol Genet Genomic Med ; 7(5): e635, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30924295

RESUMO

BACKGROUND: Nonsyndromic cleft lip and/or palate is one of the most common human birth defects worldwide that affects the lip and/or palate. The incidence of clefts varies among populations through ethnic, race, or geographical differences. The focus on Malay nonsyndromic cleft lip and/or palate (NSCL/P) is because of a scarce report on genetic study in relation to this deformity in Malaysia. We are interested to discuss about the genes that are susceptible to cause orofacial cleft formation in the family. METHODS: Genome-wide linkage analysis was carried out on eight large extended families of NSCL/P with the total of 91 individuals among Malay population using microarray platform. Based on linkage analyses findings, copy number variation (CNV) of LPHN2, SATB2, PVRL3, COL21A1, and TOX3 were identified in four large extended families that showed linkage evidence using quantitative polymerase chain reaction (qPCR) as for a validation purpose. Copy number calculated (CNC) for each genes were determined with Applied Biosystems CopyCallerTM Software v2.0. Normal CNC of the target sequence expected was set at two. RESULTS: Genome-wide linkage analysis had discovered several genes including TOX3 and COL21A1 in four different loci 4p15.2-p16.1, 6p11.2-p12.3, 14q13-q21, and 16q12.1. There was significant decreased, p < 0.05 of SATB2, COL21A1, and TOX3 copy number in extended families compared to the normal controls. CONCLUSION: Novel linkage evidence and significant low copy number of COL21A1 and TOX3 in NSCLP family was confirmed. These genes increased the risks toward NSCLP formation in that family traits.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Colágenos Fibrilares/genética , Receptores de Progesterona/genética , Fenda Labial/patologia , Fissura Palatina/patologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Malásia , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Linhagem , Fatores de Transcrição/genética
20.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 54(3): 205-208, 2019 Mar 09.
Artigo em Chinês | MEDLINE | ID: mdl-30856701

RESUMO

With the continuous development of bioinformatics technology and precision medicine, genetic mechanism investigations of genetic diseases including cleft lip and palate (CLP) have been getting more and more attention. Researchers have focused on the coding sequence of the genome and successfully found many CLP causative mutations, but there still remain some unsolved questions. In recent years, researchers' vision has gradually shifted to non-protein coding region of the genome. This article reviews several coding sequence mutations, non-protein coding variants and their genetic mechanisms discovered in CLP researches.


Assuntos
Fenda Labial , Fissura Palatina , Fenda Labial/genética , Fissura Palatina/genética , Humanos , Mutação , RNA não Traduzido
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