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2.
Niger J Clin Pract ; 23(5): 596-602, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32367864

RESUMEN

Aim: The aim of this retrospective study is to evaluate and compare the 3-dimensional (3D) crown sizes of the left and right sides of upper and lower dental arches in patients with unilateral cleft lip and palate (UCLP). Materials and Methods: Dental casts of 94 patients all in permanent dentition were included in this study. Dental casts were divided into three groups as 36 casts with unilateral left cleft lip and palate (ULCLP), 18 casts with unilateral right cleft lip and palate (URCLP), and 40 casts without cleft (control). Mesiodistal (MD), buccolingual (BL), and gingiva incisal (GI) values of each tooth were measured by scanning the dental models with a high-precision optical 3D scanner. Paired t-test and independent t-test were used for statistical analysis. Results: U1 MD, U6 MD (P = 0.001) and BL (P = 0.01), L3 GI (P = 0.05) were greater in UCLP patients on the non-cleft side while U1 GI, L1 BL, L5 MD (P = 0.001), L4 MD, and BL (P = 0.01) values were found to be greater on the cleft side. Comparison of the cleft-sides and the control group showed that MD, BL, and GI dimensions of teeth on the cleft sides were generally found to be smaller, excluding the UR7 GI values for URCLP group (P = 0.05). Conclusion: In the measurements of teeth size, reliable and repeatable results were acquired through 3D software. Tooth size asymmetries can occur non-syndromic UCLP patients in both jaws. MD, BL, and GI dimensions of teeth are mostly found to be smaller in patients with CLP.


Asunto(s)
Labio Leporino , Imagenología Tridimensional/métodos , Odontometría/métodos , Corona del Diente/diagnóstico por imagen , Estudios de Casos y Controles , Niño , Fisura del Paladar/patología , Oclusión Dental , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Maxilar , Estudios Retrospectivos , Corona del Diente/patología
3.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 55(4): 249-252, 2020 Apr 09.
Artículo en Chino | MEDLINE | ID: mdl-32268624

RESUMEN

Objective: To evaluate the changes of nasalance when cleft palate patients examined using nasometer and nasopharyngeal fiberscopy simultaneously. Methods: A total of 33 cleft palate patients from August 2004 to August 2010 were examined by nasopharyngeal fiber endoscopy and nasometer simultaneously. The nasalance of 33 voice samples was compared under two situations only nasometer and nasometer with nasopharyngeal fiberscopy. Results: The statistics showed that the nasalance value of 33 voice samples of 33 participants under different situations were no significant difference through paired t-test (P>0.05). Conclusions: Nasopharyn fiber endoscopy had no influence to the results of the nasalance value under simultaneous condition. The nasometer and nasopharyn fiber endoscopy can be applied to evaluate the velopharyngeal function of cleft palate patients simultaneously.


Asunto(s)
Fisura del Paladar , Endoscopía/métodos , Tecnología de Fibra Óptica , Insuficiencia Velofaríngea , Fisura del Paladar/diagnóstico , Fisura del Paladar/patología , Endoscopía/instrumentación , Humanos , Nariz/patología
4.
Clin Dysmorphol ; 29(1): 24-27, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30946036

RESUMEN

Microdeletion of the entire interferon regulatory factory 6 (IRF 6) gene is a rare cause of Van der Woude syndrome (VDW) with only few cases reported in medical literature. Its occurrence in multiple affected members of a family is exceptional. The aim of this presentation was to describe a Central African family with typical VDW phenotype carrying an IRF6 gene deletion. Here we reported phenotype features of members of a Central African family with VDW syndrome consisting of labioalveolar cleft, depressions of the lower lip with labial fistulae (lip pits), submucosal clefts and cleft palate. Mutation analysis by means of multiplex ligation-dependent probe amplification and chromosomal microarray revealed a 374.070 kb, deletion encompassing the entire IRF6 gene in four affected family members. Microdeletion of the entire IRF6 gene causes the classical VDW syndrome phenotype.


Asunto(s)
Anomalías Múltiples , Labio Leporino , Fisura del Paladar , Quistes , Familia , Eliminación de Gen , Factores Reguladores del Interferón/deficiencia , Labio/anomalías , Linaje , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Preescolar , Labio Leporino/genética , Labio Leporino/patología , Fisura del Paladar/genética , Fisura del Paladar/patología , Quistes/genética , Quistes/patología , República Democrática del Congo , Femenino , Humanos , Labio/patología , Masculino
5.
J Appl Oral Sci ; 27: e20180649, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31596367

RESUMEN

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.


Asunto(s)
Fisura del Paladar/genética , Metilación de ADN , Factores de Crecimiento de Fibroblastos/genética , Expresión Génica , Proteínas de Dominio T Box/genética , Animales , Fisura del Paladar/embriología , Fisura del Paladar/patología , Femenino , Factores de Crecimiento de Fibroblastos/análisis , Masculino , Ratones Endogámicos C57BL , Dominios y Motivos de Interacción de Proteínas , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Análisis de Secuencia de ADN , Proteínas de Dominio T Box/análisis
6.
EBioMedicine ; 49: 305-317, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31662288

RESUMEN

BACKGROUND: Endocrine-cerebro-osteodysplasia (ECO) syndrome is a genetic disorder associated with congenital defects of the endocrine, cerebral, and skeletal systems in humans. ECO syndrome is caused by mutations of the intestinal cell kinase (ICK) gene, which encodes a mitogen-activated protein (MAP) kinase-related kinase that plays a critical role in controlling the length of primary cilia. Lack of ICK function disrupts transduction of sonic hedgehog (SHH) signaling, which is important for development and homeostasis in humans and mice. Craniofacial structure abnormalities, such as cleft palate, are one of the most common defects observed in ECO syndrome patients, but the role of ICK in palatal development has not been studied. METHODS: Using Ick-mutant mice, we investigated the mechanisms by which ICK function loss causes cleft palate and examined pharmacological rescue of the congenital defects. FINDINGS: SHH signaling was compromised with abnormally elongated primary cilia in the developing palate of Ick-mutant mice. Cell proliferation was significantly decreased, resulting in failure of palatal outgrowth, although palatal adhesion and fusion occurred normally. We thus attempted to rescue the congenital palatal defects of Ick mutants by pharmacological activation of SHH signaling. Treatment of Ick-mutant mice with an agonist for Smoothened (SAG) rescued several congenital defects, including cleft palate. INTERPRETATIONS: The recovery of congenital defects by pharmacological intervention in the mouse models for ECO syndrome highlights prenatal SHH signaling modulation as a potential therapeutic measure to overcome congenital defects of ciliopathies.


Asunto(s)
Enfermedades del Sistema Nervioso Central/congénito , Enfermedades del Sistema Nervioso Central/metabolismo , Enfermedades del Sistema Endocrino/congénito , Enfermedades del Sistema Endocrino/metabolismo , Proteínas Hedgehog/metabolismo , Transducción de Señal , Receptor Smoothened/agonistas , Animales , Proliferación Celular , Enfermedades del Sistema Nervioso Central/genética , Cilios/metabolismo , Fisura del Paladar/patología , Modelos Animales de Enfermedad , Embrión de Mamíferos/anomalías , Embrión de Mamíferos/patología , Enfermedades del Sistema Endocrino/genética , Regulación del Desarrollo de la Expresión Génica , Ratones Noqueados , Modelos Biológicos , Mutación/genética , Paladar (Hueso)/anomalías , Paladar (Hueso)/embriología , Paladar (Hueso)/ultraestructura , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/metabolismo
7.
Genes (Basel) ; 10(10)2019 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-31652620

RESUMEN

Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palate is associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuous cleft. Although this phenotype may represent 5% of clefts of the lip and/or palate (CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducted whole exome sequencing (WES) and apply a candidate gene approach to non-syndromic discontinuous CLP individuals in order to identify genes and deleterious variants that could underlie this phenotype. We discovered loss-of-function variants in two out of the seven individuals, implicating FGFR1 and DLG1 genes, which represents almost one third of this cohort. Whole exome sequencing of clinically well-defined subgroups of CLP, such as discontinuous cleft, is a relevant approach to study CLP etiopathogenesis. It could facilitate more accurate clinical, epidemiological and fundamental research, ultimately resulting in better diagnosis and care of CLP patients. Non-syndromic discontinuous cleft lip and palate seems to have a strong genetic basis.


Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Mutación , Niño , Labio Leporino/patología , Fisura del Paladar/patología , Homólogo 1 de la Proteína Discs Large/genética , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Secuenciación del Exoma Completo/métodos
8.
Genes (Basel) ; 10(11)2019 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-31652793

RESUMEN

Orofacial clefts (OFCs) are the most frequent craniofacial birth defects. An orofacial cleft (OFC) occurs as a result of deviations in palatogenesis. Cell proliferation, differentiation, adhesion, migration and apoptosis are crucial in palatogenesis. We hypothesized that deregulation of these processes in oral keratinocytes contributes to OFC. We performed microarray expression analysis on palatal keratinocytes from OFC and non-OFC individuals. Principal component analysis showed a clear difference in gene expression with 24% and 17% for the first and second component, respectively. In OFC cells, 228 genes were differentially expressed (p < 0.001). Gene ontology analysis showed enrichment of genes involved in ß1 integrin-mediated adhesion and migration, as well as in P-cadherin expression. A scratch assay demonstrated reduced migration of OFC keratinocytes (343.6 ± 29.62 µm) vs. non-OFC keratinocytes (503.4 ± 41.81 µm, p < 0.05). Our results indicate that adhesion and migration are deregulated in OFC keratinocytes, which might contribute to OFC pathogenesis.


Asunto(s)
Adhesión Celular , Labio Leporino/genética , Fisura del Paladar/genética , Queratinocitos/metabolismo , Transcriptoma , Cadherinas/genética , Cadherinas/metabolismo , Movimiento Celular , Células Cultivadas , Labio Leporino/patología , Fisura del Paladar/patología , Femenino , Humanos , Lactante , Queratinocitos/fisiología , Masculino
9.
Mol Med Rep ; 20(4): 3326-3336, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31432193

RESUMEN

The aim of the present study was to determine the association between maternal metabolism and development of the fetal palate, and to suggest a potential non­invasive prenatal diagnostic method for fetal cleft palate (CP). Dexamethasone (DXM) was used to create a CP mouse model. A 9.4­Tesla (T) magnetic resonance spectroscopy (MRS) imager was used to measure an array of metabolites in the maternal serum, placental tissue, amniotic fluid and fetal palates. Multivariate statistical analysis was performed using SIMCA­P 14.1 software. Following DXM treatment, variations were detected in multiple metabolites in the female mice and their fetuses based on 9.4T MRS. It was indicated that in the experimental group during CP formation, leucine, valine, creatine, acetate and citrate levels in the palatal tissue were lower, whereas lactate, alanine, proline/inositol and glutamate­containing metabolite levels were higher, compared with the levels in the control group. In placental tissue and amniotic fluid, succinate and choline levels were lower in the experimental group. The relative concentrations of cholesterol and lipids in palatal tissues from mice treated with DXM were higher compared with the concentrations in tissues from mice in the control group, with the exception of (CH2)n lipids. In the placental tissue, the alteration in cholesterol level exhibited the opposite trend. Lipid levels for the different lipid forms varied and most of them were unsaturated lipids.


Asunto(s)
Fisura del Paladar , Dexametasona/efectos adversos , Embrión de Mamíferos , Desarrollo Embrionario/efectos de los fármacos , Animales , Fisura del Paladar/inducido químicamente , Fisura del Paladar/embriología , Fisura del Paladar/metabolismo , Fisura del Paladar/patología , Dexametasona/farmacología , Modelos Animales de Enfermedad , Embrión de Mamíferos/embriología , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Femenino , Espectroscopía de Resonancia Magnética , Ratones
10.
Am J Orthod Dentofacial Orthop ; 156(2): 257-265, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31375236

RESUMEN

INTRODUCTION: Children with unilateral cleft lip and palate (UCLP) exhibit snoring and mouth breathing. They are also reported to show obstructive sleep apnea syndrome. However, their upper airway ventilation condition is not clearly understood. Therefore, this study was performed to evaluate upper airway ventilation condition in children with UCLP with the use of computational fluid dynamics. METHODS: Twenty-one children (12 boys, 9 girls; mean age 9.1 years) with UCLP and 25 children (13 boys, 12 girls; mean age 9.2 years) without UCLP who required orthodontic treatment underwent cone-beam computed tomography (CBCT). Nasal resistance and upper airway ventilation condition were evaluated with the use of computational fluid dynamics from CBCT data. The groups were compared with the use of Mann-Whitney U tests and Student t tests. RESULTS: Nasal resistance of the UCLP group (0.97 Pa/cm3/s) was significantly higher than that of the control group (0.26 Pa/cm3/s; P < 0.001). Maximal pressure of the upper airway (335.02 Pa) was significantly higher in the UCLP group than in the control group (67.57 Pa; P < 0.001). Pharyngeal airway (from choanae to base of epiglottis) pressure in the UCLP group (140.46 Pa) was significantly higher than in the control group (15.92 Pa; P < 0.02). CONCLUSIONS: Upper airway obstruction in children with UCLP resulted from both nasal and pharyngeal airway effects.


Asunto(s)
Labio Leporino/patología , Fisura del Paladar/patología , Tomografía Computarizada de Haz Cónico/métodos , Hidrodinámica , Laringe/anatomía & histología , Nariz/anatomía & histología , Tonsila Faríngea/anatomía & histología , Puntos Anatómicos de Referencia , Niño , Labio Leporino/diagnóstico por imagen , Fisura del Paladar/diagnóstico por imagen , Epiglotis/anatomía & histología , Epiglotis/diagnóstico por imagen , Femenino , Humanos , Hueso Hioides/anatomía & histología , Imagenología Tridimensional/métodos , Laringe/diagnóstico por imagen , Maloclusión de Angle Clase I , Nasofaringe/anatomía & histología , Nasofaringe/diagnóstico por imagen , Nariz/diagnóstico por imagen , Respiración , Apnea Obstructiva del Sueño
11.
BMC Med Genomics ; 12(1): 93, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31262291

RESUMEN

BACKGROUND: Cleft palate (CP) is the second most common congenital birth defect; however, the relationship between CP-associated genes and epigenetic regulation remains largely unknown. In this study, we investigated the contribution of microRNAs (miRNAs) to cell proliferation and regulation of genes involved in CP development. METHODS: In order to identify all genes for which mutations or association/linkage have been found in individuals with CP, we conducted a systematic literature search, followed by bioinformatics analyses for these genes. We validated the bioinformatics results experimentally by conducting cell proliferation assays and miRNA-gene regulatory analyses in cultured human palatal mesenchymal cells treated with each miRNA mimic. RESULTS: We identified 131 CP-associated genes in the systematic review. The bioinformatics analysis indicated that the CP genes were associated with signaling pathways, microRNAs (miRNAs), metabolic pathways, and cell proliferation. A total 17 miRNAs were recognized as potential modifiers of human CP genes. To validate miRNA function in cell proliferation, a main cause of CP, we conducted cell proliferation/viability assays for the top 11 candidate miRNAs from our bioinformatics analysis. Overexpression of miR-133b, miR-374a-5p, and miR-4680-3p resulted in a more than 30% reduction in cell proliferation activity in human palatal mesenchymal cell cultures. We found that several downstream target CP genes predicted by the bioinformatics analyses were significantly downregulated through induction of these miRNAs (FGFR1, GCH1, PAX7, SMC2, and SUMO1 by miR-133b; ARNT, BMP2, CRISPLD1, FGFR2, JARID2, MSX1, NOG, RHPN2, RUNX2, WNT5A and ZNF236 by miR-374a-5p; and ERBB2, JADE1, MTHFD1 and WNT5A by miR-4680-3p) in cultured cells. CONCLUSIONS: Our results indicate that miR-374a-5p, miR-4680-3p, and miR-133b regulate expression of genes that are involved in the etiology of human CP, providing insight into the association between CP-associated genes and potential targets of miRNAs in palate development.


Asunto(s)
Fisura del Paladar/genética , Fisura del Paladar/patología , Regulación de la Expresión Génica/genética , MicroARNs/genética , Paladar (Hueso)/patología , Proliferación Celular/genética , Células Cultivadas , Biología Computacional , Epigénesis Genética , Humanos , Paladar (Hueso)/metabolismo
12.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-31340433

RESUMEN

Lysyl oxidase like 3 (LOXL3) is a copper-dependent amine oxidase responsible for the crosslinking of collagen and elastin in the extracellular matrix. LOXL3 belongs to a family including other members: LOX, LOXL1, LOXL2, and LOXL4. Autosomal recessive mutations are rare and described in patients with Stickler syndrome, early-onset myopia and non-syndromic cleft palate. Along with an essential function in embryonic development, multiple biological functions have been attributed to LOXL3 in various pathologies related to amino oxidase activity. Additionally, various novel roles have been described for LOXL3, such as the oxidation of fibronectin in myotendinous junction formation, and of deacetylation and deacetylimination activities of STAT3 to control of inflammatory response. In tumors, three distinct roles were described: (1) LOXL3 interacts with SNAIL and contributes to proliferation and metastasis by inducing epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells; (2) LOXL3 is localized predominantly in the nucleus associated with invasion and poor gastric cancer prognosis; (3) LOXL3 interacts with proteins involved in DNA stability and mitosis completion, contributing to melanoma progression and sustained proliferation. Here we review the structure, function and activity of LOXL3 in normal and pathological conditions and discuss the potential of LOXL3 as a therapeutic target in various diseases.


Asunto(s)
Aminoácido Oxidorreductasas/genética , Artritis/genética , Fisura del Paladar/genética , Enfermedades del Tejido Conjuntivo/genética , Matriz Extracelular/genética , Pérdida Auditiva Sensorineural/genética , Miopía/genética , Neoplasias/genética , Desprendimiento de Retina/genética , Aminoácido Oxidorreductasas/química , Aminoácido Oxidorreductasas/metabolismo , Artritis/enzimología , Artritis/patología , Fisura del Paladar/enzimología , Fisura del Paladar/patología , Colágeno/química , Colágeno/genética , Colágeno/metabolismo , Enfermedades del Tejido Conjuntivo/enzimología , Enfermedades del Tejido Conjuntivo/patología , Elastina/química , Elastina/genética , Elastina/metabolismo , Transición Epitelial-Mesenquimal/genética , Matriz Extracelular/química , Matriz Extracelular/enzimología , Regulación de la Expresión Génica , Pérdida Auditiva Sensorineural/enzimología , Pérdida Auditiva Sensorineural/patología , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Miopía/enzimología , Miopía/patología , Neoplasias/enzimología , Neoplasias/patología , Especificidad de Órganos , Desprendimiento de Retina/enzimología , Desprendimiento de Retina/patología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo
13.
Lasers Med Sci ; 34(8): 1699-1703, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31187297

RESUMEN

Post-surgical scars of cleft lip patients can lead to abnormal lip activity, which causes deficient maxillary growth. The aim of the present study was to assess the effect of laser therapy on the appearance and electrical activity of the upper lip in cleft lip and palate patients. Twelve patients with cleft lip and palate participated in this study. All patients had surgically repaired the cleft lip at the age of about 3-6 months. The lip scars underwent five fractional CO2 laser treatment sessions with a 4-week interval. Improvement of the quality of the skin texture was recorded according to quartile grading scale based on photographs taken before and 1 month after treatment. Patients' satisfaction survey was also recorded using Patient Scar Assessment Questionnaire (PSAQ) before and after laser therapy. Moreover, the EMG activity of the upper lip muscle was measured before and after treatment. According to dermatologists, the improvement of scar appearance ranged from 0.5 to 3, with a mean of 1.29 ± 0.86. Mean scores of the scar appearance (p < 0.001), symptoms (p = 0.003), and scar consciousness (p < 0.001) subscales of the PSAQ questionnaire had significantly increased after treatment. The EMG recording of the upper lip had decreased significantly after laser treatment at rest (p = 0.009) and maximum lip compression (p = 0.007). The fractional CO2 laser is an effective method for treating old scars of the cleft lip with a significant change in the opinion of patients about their scar appearance. Also, the therapy can help to reduce the EMG activity of the upper lip at rest.


Asunto(s)
Cicatriz/etiología , Cicatriz/cirugía , Labio Leporino/cirugía , Fisura del Paladar/cirugía , Láseres de Gas/uso terapéutico , Cicatriz/patología , Fisura del Paladar/patología , Electrodos , Electromiografía , Femenino , Humanos , Labio/patología , Labio/fisiopatología , Labio/cirugía , Resultado del Tratamiento , Adulto Joven
14.
Genet Epidemiol ; 43(6): 704-716, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31172578

RESUMEN

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.


Asunto(s)
Encéfalo/anomalías , Labio Leporino/clasificación , Labio Leporino/genética , Fisura del Paladar/clasificación , Fisura del Paladar/genética , Sitios Genéticos , Marcadores Genéticos , Pruebas Genéticas/métodos , Estudio de Asociación del Genoma Completo/métodos , Fenotipo , Encéfalo/patología , Labio Leporino/patología , Fisura del Paladar/patología , Humanos , Transcriptoma
15.
J Appl Oral Sci ; 27: e20180434, 2019 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-31215598

RESUMEN

This study aimed to compare the linear dimensions of the dental arches of adult patients with complete unilateral cleft lip and palate (UCLP) after orthodontic and prosthetic treatment with fixed partial dentures (FPD) to patients without clefts, using 3D technology. This retrospective longitudinal study sample consisted of 35 subjects divided into two groups. Included in this sample were 15 complete UCLP individuals who had received orthodontic treatment before rehabilitation with a fixed partial denture (FG), as well as 20 patients without cleft as control group (CG). All patients were aged between 18 and 30 years. Digital dental casts were obtained in two stages: (T1) end of orthodontic treatment and (T2) one year after prosthetic rehabilitation (FG); and (T1) end of orthodontic treatment and (T2) one year after removal of the orthodontic appliance (CG). Intercanine, interfirst premolar and intermolar distances, and incisor-molar length were obtained. A precalibrated and trained examiner performed the assessments. Intergroup differences between T2 and T1 were compared between the groups using the t test or Mann-Whitney test with a significance level of 5% (p<0.05). The intercanine distance variation (T2-T1) showed statistical difference (p=0.005) increasing in the FG group and decreasing in the CG group. In the interfirst premolar distance variation, FG decreased, while CG increased with statistically significant difference (p=0.008). The intercanine distance of individuals with cleft showed stability, while that of the CG had no stability. The CG showed stability in the interfirst premolar distance, while FG had no stability. These findings showed that the FPD is capable of restricting orthodontic results, leading to a stabilization of the dental arches.


Asunto(s)
Labio Leporino/rehabilitación , Fisura del Paladar/rehabilitación , Arco Dental/patología , Prótesis Dental de Soporte Implantado/métodos , Imagenología Tridimensional/métodos , Ortodoncia Correctiva/métodos , Adolescente , Adulto , Puntos Anatómicos de Referencia , Labio Leporino/patología , Fisura del Paladar/patología , Femenino , Humanos , Masculino , Maxilar/patología , Aparatos Ortodóncicos , Valores de Referencia , Estudios Retrospectivos , Estadísticas no Paramétricas , Resultado del Tratamiento , Adulto Joven
16.
Dis Model Mech ; 12(6)2019 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-31171577

RESUMEN

Core binding factor ß (Cbfb) is a cofactor of the Runx family of transcription factors. Among these transcription factors, Runx1 is a prerequisite for anterior-specific palatal fusion. It was previously unclear, however, whether Cbfb served as a modulator or as an obligatory factor in the Runx signaling process that regulates palatogenesis. Here, we report that Cbfb is essential and indispensable in mouse anterior palatogenesis. Palatal fusion in Cbfb mutants is disrupted owing to failed disintegration of the fusing epithelium specifically at the anterior portion, as observed in Runx1 mutants. In these mutants, expression of TGFB3 is disrupted in the area of failed palatal fusion, in which phosphorylation of Stat3 is also affected. TGFB3 protein has been shown to rescue palatal fusion in vitro TGFB3 also activated Stat3 phosphorylation. Strikingly, the anterior cleft palate in Cbfb mutants is further rescued by pharmaceutical application of folic acid, which activates suppressed Stat3 phosphorylation and Tgfb3 expression in vitro With these findings, we provide the first evidence that Cbfb is a prerequisite for anterior palatogenesis and acts as an obligatory cofactor in the Runx1/Cbfb-Stat3-Tgfb3 signaling axis. Furthermore, the rescue of the mutant cleft palate using folic acid might highlight potential therapeutic targets aimed at Stat3 modification for the prevention and pharmaceutical intervention of cleft palate.


Asunto(s)
Fisura del Paladar/tratamiento farmacológico , Fisura del Paladar/patología , Subunidad beta del Factor de Unión al Sitio Principal/deficiencia , Ácido Fólico/uso terapéutico , Animales , Fisura del Paladar/genética , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Epitelio/efectos de los fármacos , Epitelio/patología , Ácido Fólico/farmacología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Mutantes , Modelos Biológicos , Mutación/genética , Organogénesis/efectos de los fármacos , Paladar (Hueso)/anomalías , Paladar (Hueso)/embriología , Paladar (Hueso)/patología , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Crecimiento Transformador beta3/metabolismo
17.
Int J Mol Sci ; 20(9)2019 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-31052503

RESUMEN

Craniofacial bone defect anomalies affect both soft and hard tissues and can be caused by trauma, bone recessions from tumors and cysts, or even from congenital disorders. On this note, cleft/lip palate is the most prevalent congenital craniofacial defect caused by disturbed embryonic development of soft and hard tissues around the oral cavity and face area, resulting in most cases, of severe limitations with chewing, swallowing, and talking as well as problems of insufficient space for teeth, proper breathing, and self-esteem problems as a consequence of facial appearance. Spectacular advances in regenerative medicine have arrived, giving new hope to patients that can benefit from new tissue engineering therapies based on the supportive action of 3D biomaterials together with the synergic action of osteo-inductive molecules and recruited stem cells that can be driven to the process of bone regeneration. However, few studies have focused on the application of tissue engineering to the regeneration of the cleft/lip and only a few have reported significant advances to offer real clinical solutions. This review provides an updated and deep analysis of the studies that have reported on the use of advanced biomaterials and cell therapies for the regeneration of cleft lip and palate regeneration.


Asunto(s)
Materiales Biocompatibles/uso terapéutico , Labio Leporino/terapia , Fisura del Paladar/terapia , Medicina Regenerativa/métodos , Animales , Labio Leporino/epidemiología , Labio Leporino/patología , Labio Leporino/fisiopatología , Fisura del Paladar/epidemiología , Fisura del Paladar/patología , Fisura del Paladar/fisiopatología , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapéutico , Humanos , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Osteogénesis/efectos de los fármacos , Trasplante de Células Madre/métodos , Ingeniería de Tejidos/métodos
18.
Mol Med Rep ; 20(1): 513-528, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31115538

RESUMEN

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.


Asunto(s)
Encéfalo/anomalías , Labio Leporino/genética , Fisura del Paladar/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Encéfalo/patología , Preescolar , Labio Leporino/sangre , Labio Leporino/patología , Fisura del Paladar/sangre , Fisura del Paladar/patología , Biología Computacional , Femenino , Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , MicroARNs/sangre , ARN Largo no Codificante/sangre , ARN Mensajero/sangre , ARN Mensajero/genética , Transcriptoma/genética
19.
BMC Genomics ; 20(1): 349, 2019 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-31068123

RESUMEN

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.


Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Fisura del Paladar/genética , Polimorfismo de Nucleótido Simple , Porcinos/genética , Anomalías Múltiples/patología , Animales , Fisura del Paladar/patología , Femenino , Masculino , Síndrome , Secuenciación Completa del Genoma
20.
Ann Anat ; 224: 41-46, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30953811

RESUMEN

AIM: The aim of this study was to evaluate palatal vertical bone thickness and density in relation to soft tissue on the hard palate for better selection of adequate bone regions for the insertion of orthodontic mini-implants (MIs) in cleft palate patients. MATERIALS AND METHODS: Cone beam computed tomography scans (CBCT) were obtained from 60 patients (mean age range 9-12). The study population included patients with isolate right side cleft palate formation (n = 20; 6 females; 14 males), left side cleft palate formation (n = 20; 9 females; 11 males) and without cleft formation as control group (n = 20; 15 females; 5 males). Bone and soft tissue measurements were performed vertical at a 90° angle to the bone surface, on previously defined measurement points (n = 88) on the hard palate. Bone density was measured on ten vertical layers in caudo-cranial direction. RESULTS: In non-cleft patient the highest bone thickness was in the anterior palate and decreased significantly in posterior direction. In patients with right and left cleft palate, the highest vertical bone level could be observed at the palatal premaxillary border opposite to the cleft side. Patients in the control group showed a significantly lower vertical soft tissue thickness than patients with palatal cleft formation. The evaluation of bone density showed no significant differences in all three groups. CONCLUSION: The results suggest that the favorable region for orthodontic MI placement is in the similar anatomical region compared to non-cleft patients, but differs from one side in each group. In unilateral cleft palate patients, the highest bone level was found on the anterior palate side opposite to the cleft side, indicating the most effective region for MIs placement.


Asunto(s)
Fisura del Paladar/patología , Paladar Duro/patología , Anclas para Sutura/normas , Densidad Ósea , Estudios de Casos y Controles , Niño , Fisura del Paladar/diagnóstico por imagen , Fisura del Paladar/cirugía , Tomografía Computarizada de Haz Cónico , Implantes Dentales/normas , Femenino , Humanos , Imagenología Tridimensional , Masculino , Ortodoncia/métodos , Paladar Duro/diagnóstico por imagen , Paladar Duro/fisiología , Paladar Duro/cirugía , Proyectos Piloto , Estudios Retrospectivos
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