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1.
Biomed Res Int ; 2019: 2183720, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781599

RESUMO

The etiology of hypodontia is complex, in which both genetic and environmental factors can be related. The main objective of our study was to contribute to elucidating the genetic background of nonsyndromic hypodontia (NSH). In this order, we selected 97 NSH subjects (70 females and 27 males) from patients referred to orthodontic treatment, and we matched to each NSH subject a control by age and sex. DNA was obtained from epithelial cells from the oral mucosa. Genotyping of the PAX9 (rs4904155 and rs61754301), MSX1 (rs8670 and rs12532), and AXIN2 (rs2240308) SNPs was performed by using TaqMan SNP Genotyping Assays on a real-time PCR system. Single-nucleotide polymorphisms (SNPs) were studied for the whole NSH group and for frontal and lateral agenesis NSH subjects separately. Our results showed that the variant genotype (p=0.0008, OR = 2.9, 95% CI = 1.58-5.3) and variant T allele (p=0.0002, OR = 2.65, 95% CI = 1.6-4.39) of the MSX1 rs8670 SNP increased the risk of hypodontia in the studied population when the whole NSH group was compared with controls. The variant genotype of the MSX1 rs8670 SNP was the most frequent in frontal agenesis; meanwhile in the lateral agenesis NSH group, the AXIN2 rs2240308 SNP showed a higher frequency of the variant genotype, with a trend towards statistical significance. In conclusion, the results of the present study showed that the variant genotype and variant T allele of the MSX1 rs8670 SNP increased the risk of hypodontia in the studied population. The presence of the variant A allele of AXIN2 rs2240308 is associated with frontal agenesis but not with lateral agenesis.


Assuntos
Anodontia/genética , Proteína Axina/genética , Fator de Transcrição MSX1/genética , Fator de Transcrição PAX9/genética , Adolescente , Adulto , Alelos , Anodontia/fisiopatologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
2.
PLoS Genet ; 15(10): e1008357, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31609978

RESUMO

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/genética , Fator de Transcrição PAX9/genética , Alelos , Encéfalo/fisiopatologia , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Dosagem de Genes/genética , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
3.
J Orthod ; 46(1): 14-19, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31056064

RESUMO

OBJECTIVE: Maxillary canines are the second-most commonly impacted teeth. About two-thirds of the impacted maxillary canines are palatally impacted. Studies in the past have shown that 40% of cases with palatal impaction of maxillary canines presented with agenesis of third molars. Sporadic agenesis of third molars have been associated with polymorphisms in the MSX1 and PAX9 genes. The present study aims at evaluating the association between polymorphisms of PAX9, MSX1 and palatally impacted canines in a random population sample. DESIGN AND SETTING: Fifty individuals with palatally impacted maxillary canines and 50 gender and age-matched controls were included in this study. METHODS: Single nucleotide polymorphisms (SNPs), rs12532 of MSX1 and rs2073247 of PAX9, were genotyped using polymerase chain reaction and restriction fragment length polymorphism. The significance of the differences among the groups was assessed by odds ratio and Chi-squared test with a 95% confidence interval. RESULTS: Single nucleotide polymorphisms rs12532 [MSX1] and rs 2073247 [PAX9] showed a statistically significant association with palatal impaction of maxillary canines. In addition, the combined presence of the AG/CT genotypes of these genes in an individual caused a significant increase in the risk for palatal impaction. CONCLUSION: These results suggest that the rs12532 and rs2073247 polymorphisms of genes MSX1 and PAX9 are positively associated with palatal impaction of maxillary canines. Future studies investigating various other SNPs of these genes in a larger sample of different populations could provide clinching details.


Assuntos
Fator de Transcrição MSX1 , Fator de Transcrição PAX9 , Dente Impactado , Dente Canino , Humanos , Maxila , Dente Serotino , Razão de Chances , Dente Impactado/genética
4.
Clin Oral Investig ; 23(11): 4107-4111, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30809714

RESUMO

OBJECTIVE: Tooth agenesis is one of the most common craniofacial developmental anomalies. In hypodontia, one to five teeth are missing, whereas oligodontia refers to the absence of at least six teeth, excluding the third molars. Mutations in several genes including MSX1, PAX9, AXIN2, and WNT10A have been shown to cause non-syndromic tooth agenesis. Regional odontodysplasia (RO), also known as "ghost teeth," is a rare developmental anomaly of tooth formation affecting both dentitions. Some possible causes of RO have been suggested, yet the etiology remains unknown. Because the phenotypes of both oligodontia and RO co-occur in one Finnish family, the aim here was to investigate the genetic etiology of the two conditions. MATERIALS AND METHODS: A mutation screening of the genes MSX1, PAX9, AXIN2, and WNT10A was performed for the family members of a RO patient and family history of oligodontia. RESULTS: An initiation codon mutation of the PAX9 gene was found in the proband and segregating with oligodontia in the family. CONCLUSIONS: The etiology of regional odontodysplasia (RO) may be genetic and the same genes can be involved both in RO and tooth agenesis. CLINICAL RELEVANCE: Our results give new insights into the etiology of regional odontodysplasia, yet further results are needed.


Assuntos
Anodontia , Odontodisplasia , Fator de Transcrição PAX9 , Anodontia/genética , Códon de Iniciação , Humanos , Fator de Transcrição MSX1 , Mutação , Odontodisplasia/genética , Fator de Transcrição PAX9/genética , Linhagem
5.
Oral Dis ; 25(1): 234-241, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30256498

RESUMO

OBJECTIVE: To investigate a novel gene mutation in a Chinese patient with non-syndromic hypodontia. SUBJECTS AND METHODS: Mutation analysis was carried out by whole exome sequencing. Bioinformatics tools were used for the biophysical predictions of the mutative protein. Luciferase reporter assay was performed to analyse the effects of mutation on protein function. PAX9 and BMP4 gene expression from mutant cells was detected by qRT-PCR. RESULTS: A novel heterozygous mutation (c.G1057A) was detected in the patient but was not found in the controls. The novel missense mutation led to a Val111Met substitution in the paired box domain which was completely conserved evolutionarily, as analysed by dbNSFP. The mutation was predicted to be disease-causing and harmful using MutationTaster and CADD, respectively. Protean of Lasergene showed that this mutation may lead to ß-region shortening in the mutant protein compared to the wild type. Luciferase reporter assay indicated that the mutated protein reduced the transactivation activity of PAX9. This mutation led to increased levels of PAX9 transcript and reduced levels of BMP4 transcript, likely due to compensatory activation and lower transactivation activity of mutant PAX9. CONCLUSION: This novel mutation (c.G1057A) in PAX9 caused hypodontia by altering PAX9 gene function and downregulating BMP4 gene expression.


Assuntos
Anodontia/genética , Fator de Transcrição PAX9/genética , Adolescente , Análise Mutacional de DNA , Feminino , Humanos , Mutação , Linhagem , Sequenciamento Completo do Exoma
6.
Oral Dis ; 25(2): 523-534, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30417976

RESUMO

OBJECTIVES: To identify potentially pathogenic mutations for tooth agenesis by whole-exome sequencing. SUBJECTS AND METHODS: Ten Chinese families including five families with ectodermal dysplasia (syndromic tooth agenesis) and five families with selective tooth agenesis were included. Whole-exome sequencing was performed using genomic DNA. Potentially pathogenic mutations were identified after data filtering and screening. The pathogenicity of novel variants was investigated by segregation analysis, in silico analysis, and functional studies. RESULTS: One novel mutation (c.441_442insACTCT) and three reported mutations (c.252delT, c.463C>T, and c.1013C>T) in EDA were identified in families with ectodermal dysplasia. The novel EDA mutation was co-segregated with phenotype. A functional study revealed that NF-κB activation was compromised by the identified mutations. The secretion of active EDA was also compromised detection by western blotting. Novel Wnt10A mutations (c.521T>C and c.653T>G) and EVC2 mutation (c.1472C>T) were identified in families with selective tooth agenesis. The Wnt10A c.521T>C mutation and the EVC2 c.1472C>T mutation were considered as pathogenic for affecting highly conserved amino acids, co-segregated with phenotype and predicted to be disease-causing by SIFT and PolyPhen2. Moreover, several reported mutations in PAX9, Wnt10A, and FGFR3 were also detected. CONCLUSIONS: Our study expanded our knowledge on tooth agenesis spectrum by identifying novel variants.


Assuntos
Anodontia/genética , Displasia Ectodérmica/genética , Ectodisplasinas/genética , Proteínas/genética , Proteínas Wnt/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , China , Ectodisplasinas/metabolismo , Feminino , Mutação da Fase de Leitura , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Fator de Transcrição PAX9/genética , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/genética , Transfecção , Sequenciamento Completo do Exoma , Adulto Jovem
7.
Oral Dis ; 25(3): 646-651, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29969831

RESUMO

Tooth agenesis (TA) is one of the most common developmental anomalies that affects the number of teeth. An extensive analysis of publicly accessible databases revealed 15 causative genes responsible for nonsyndromic TA, along with their signaling pathways in Wnt/ß-catenin, TGF-ß/BMP, and Eda/Edar/NF-κB. However, genotype-phenotype correlation analysis showed that most of the causal genes are also responsible for syndromic TA or other conditions. In a total of 198 different mutations of the 15 genes responsible for nonsyndromic TA, 182 mutations (91.9%) are derived from seven genes (AXIN2, EDA, LRP6, MSX1, PAX9, WNT10A, and WNT10B) compared with the remaining 16 mutations (8.1%) identified in the remaining eight genes (BMP4, DKK1, EDAR, EDARADD, GREM2, KREMEN1, LTBP3, and SMOC2). Furthermore, specificity analysis in terms of the ratio of nonsyndromic TA mutations versus syndromic mutations in each of the aforementioned seven genes showed a 98.2% specificity rate in PAX9, 58.9% in WNT10A, 56.6% in MSX1, 41.2% in WNT10B, 31.4% in LRP6, 23.8% in AXIN2%, and 8.4% in EDA. These findings underscore an important role of the Wnt and Wnt-associated pathways in the genetic etiology of this heterozygous disease and shed new lights on the discovery of novel molecular mechanisms associated with tooth agenesis.


Assuntos
Anodontia/genética , Proteína Morfogenética Óssea 4/genética , Ectodisplasinas/genética , Receptor Edar/genética , Fator de Crescimento Transformador beta/genética , Via de Sinalização Wnt/genética , Animais , Proteína Axina/genética , Proteínas de Ligação ao Cálcio/genética , Proteína de Domínio de Morte Associada a Edar/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Ligação a TGF-beta Latente/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Fator de Transcrição MSX1/genética , Proteínas de Membrana/genética , Mutação , NF-kappa B/genética , Fator de Transcrição PAX9/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Wnt/genética
8.
J Dent Res ; 98(3): 277-287, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30583699

RESUMO

Cleft palate, a common congenital deformity, can arise from disruptions in any stage of palatogenesis, including palatal shelf growth, elevation, adhesion, and fusion. Paired box gene 9 (Pax9) is recognized as a vital regulator of palatogenesis with great relevance to cleft palate in humans and mice. Pax9-deficient murine palatal shelves displayed deficient elongation, postponed elevation, failed contact, and fusion. Pax9 is expressed in epithelium and mesenchyme, exhibiting a dynamic expression pattern that changes according to the proceeding of palatogenesis. Recent studies highlighted the Pax9-related genetic interactions and their critical roles during palatogenesis. During palate growth, PAX9 interacts with numerous molecules and members of pathways (e.g., OSR2, FGF10, SHOS2, MSX1, BARX1, TGFß3, LDB1, BMP, WNT ß-catenin dependent, and EDA) in the mesenchyme and functions as a key mediator in epithelial-mesenchymal communications with FGF8, TBX1, and the SHH pathway. During palate elevation, PAX9 is hypothesized to mediate the time point of the elevation event in the anterior and posterior parts of the palatal shelves. The delayed elevation of Pax9 mutant palatal shelves probably results from abnormal expressions of a series of genes ( Osr2 and Bmpr1a) leading to deficient palate growth, abnormal tongue morphology, and altered hyaluronic acid distribution. The interactions between PAX9 and genes encoding the OSR2, TGFß3, and WNT ß-catenin-dependent pathways provide evidence that PAX9 might participate in the regulation of palate fusion. This review summarizes the current understanding of PAX9's functions and emphasizes the interactions between PAX9 and vital genes during palatogenesis. We hope to provide some clues for further exploration of the function and mechanism of PAX9, especially during palate elevation and fusion events.


Assuntos
Fissura Palatina , Regulação da Expressão Gênica no Desenvolvimento , Fator de Transcrição PAX9/genética , Animais , Proteínas de Ligação a DNA , Humanos , Proteínas com Domínio LIM , Mesoderma , Camundongos , Palato , Via de Sinalização Wnt
9.
PLoS One ; 13(9): e0202747, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30208064

RESUMO

Snail2 is a zinc-finger transcription factor best known to repress expression of genes encoding cell adherence proteins to facilitate induction of the epithelial-to-mesenchymal transition. While this role has been best documented in the developmental migration of the neural crest and mesoderm, here we expand on previously reported preliminary findings that morpholino knock-down of snai2 impairs the generation of hematopoietic stem cells (HSCs) during zebrafish development. We demonstrate that snai2 morphants fail to initiate HSC specification and show defects in the somitic niche of migrating HSC precursors. These defects include a reduction in sclerotome markers as well as in the Notch ligands dlc and dld, which are known to be essential components of HSC specification. Accordingly, enforced expression of the Notch1-intracellular domain was capable of rescuing HSC specification in snai2 morphants. To parallel our approach, we obtained two mutant alleles of snai2. In contrast to the morphants, homozygous mutant embryos displayed no defects in HSC specification or in sclerotome development, and mutant fish survive into adulthood. However, when these homozygous mutants were injected with snai2 morpholino, HSCs were improperly specified. In summary, our morpholino data support a role for Snai2 in HSC development, whereas our mutant data suggest that Snai2 is dispensable for this process. Together, these findings further support the need for careful consideration of both morpholino and mutant phenotypes in studies of gene function.


Assuntos
Fatores de Transcrição da Família Snail/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Sequência de Aminoácidos , Animais , Diferenciação Celular , Embrião não Mamífero/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genótipo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Morfolinos/metabolismo , Mutagênese Sítio-Dirigida , Fator de Transcrição PAX9/metabolismo , Fenótipo , Receptores Notch/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Fatores de Transcrição da Família Snail/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/metabolismo
10.
J Pathol ; 244(4): 386-388, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29344962

RESUMO

The pathogenesis of oro-oesophaeal squamous cell carcinoma is causally linked to the consumption of alcohol. Beyond the carcinogenic effects of ethanol and its metabolites via DNA damage, the precise mechanisms by which alcohol drives tumourigenesis remain to be fully elucidated. A novel contributor now revealed is aberrant differentiation and proliferation mediated by suppression of PAX9, a key regulator of normal squamous maturation in oro-oesophageal tissues. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Carcinogênese , Diferenciação Celular , Regulação para Baixo , Etanol , Humanos , Fator de Transcrição PAX9/genética , Reino Unido
11.
J Pathol ; 244(2): 164-175, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29055049

RESUMO

PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, Pax9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or Pax9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Diferenciação Celular , Transformação Celular Neoplásica/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Fator de Transcrição PAX9/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Neoplasias da Língua/metabolismo , Consumo de Bebidas Alcoólicas/efeitos adversos , Animais , Linhagem Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Metilação de DNA , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição PAX9/genética , Fatores de Transcrição Box Pareados/deficiência , Fatores de Transcrição Box Pareados/genética , Regiões Promotoras Genéticas , Fatores de Risco , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias da Língua/genética , Neoplasias da Língua/patologia , Transcriptoma
12.
Eur J Oral Sci ; 126(1): 24-32, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29114927

RESUMO

Non-syndromic tooth agenesis (NSTA) is the most common developmental anomaly in humans. Several studies have been conducted on dental agenesis and numerous genes have been identified. However, the pathogenic mechanisms responsible for NSTA are not clearly understood. We studied a group of 28 patients with sporadic NSTA and nine patients with a family history of tooth agenesis. We focused on four genes - paired box 9 (PAX9), Wnt family member 10A (WNT10A), msh homeobox 1 (MSX1), and axin 2 (AXIN2) - using direct Sanger sequencing of the exons and intron-exon boundaries. The most prevalent variants identified in PAX9 and AXIN2 genes were analyzed using the chi-square test. The sequencing results revealed a number of variants in the AXIN2 gene, including one novel missense mutation in one patient with agenesis of a single second premolar. We also identified one variant in the AXIN2 gene as being a putative risk factor for tooth agenesis. Only one missense mutation was identified in the WNT10A gene and this mutation was found in two patients. Interestingly, WNT10A is reported as the most prevalent gene mutated in the European population with NSTA.


Assuntos
Anodontia/genética , Proteína Axina/genética , Fator de Transcrição MSX1/genética , Mutação , Fator de Transcrição PAX9/genética , Proteínas Wnt/genética , Anodontia/diagnóstico por imagem , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo , Polimorfismo Genético , Radiografia Panorâmica
13.
J Dent Res ; 97(2): 155-162, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28910570

RESUMO

Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with exception of families in which DNA analysis was not available). In 1 family ( n = 6), 2 individuals harbored both the PAX9 c.592delG mutation and a heterozygous missense mutation (c.739C>T) in the MSX1 gene. Clinical characterization of families segregating a PAX9 mutation reveal that all affected individuals were missing the mandibular second molar and their maxillary central incisors are most susceptible to microdontia. A significant reduction of bitter taste perception was documented in individuals harboring PAX9 mutations ( n = 3). Functional studies revealed that PAX9 haploinsufficiency or a loss of function of the PAX9 protein underlies tooth agenesis.


Assuntos
Anodontia/genética , Análise Mutacional de DNA , Fator de Transcrição PAX9/genética , Adolescente , Adulto , Criança , China , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Imunofluorescência , Estudos de Associação Genética , Humanos , Fator de Transcrição MSX1/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Reação em Cadeia da Polimerase , Distúrbios do Paladar/genética
14.
Am J Hum Genet ; 101(6): 913-924, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198719

RESUMO

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.


Assuntos
Orelha/anatomia & histologia , Herança Multifatorial/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Animais , Região Branquial/anatomia & histologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Receptor Edar/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Camundongos , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Fator de Transcrição PAX9/genética , Proteínas/genética , Receptores Acoplados a Proteínas-G/genética , Proteínas Ribossômicas/genética , Fatores de Transcrição/genética , Adulto Jovem
15.
PLoS One ; 12(10): e0186260, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29023497

RESUMO

Transcription factors PAX9 and MSX1 play crucial roles in the development of permanent teeth at the bud stage, and their loss-of-function variants have been associated with congenital tooth agenesis. We sequenced the coding regions of the PAX9 and MSX1 genes from nine patients with non-syndromic tooth agenesis, and identified a missense mutation, P20L, of PAX9 in a single familial case involving three patients in two generations. Identical mutation was previously reported by other authors, but has not been characterized in detail. The mutation was located in a highly conserved N-terminal subdomain of the paired domain and co-segregated as a heterozygote with tooth agenesis. The patients showed defects primarily in the first and second molars, which is typical for cases attributable to PAX9 mutation. Luciferase reporter assay using the 2.3-kb promoter region of BMP4 and electrophoretic mobility shift assay using the CD19-2(A-ins) sequence revealed that P20L substitution eliminated most of the transactivation activity and specific DNA binding activity of PAX9 under the experimental conditions we employed, while some residual activity of the mutant was evident in the former assay. The hypomorphic nature of the variant may explain the relatively mild phenotype in this case, as compared with other PAX9 pathogenic variants such as R26W.


Assuntos
Anodontia/genética , Fator de Transcrição PAX9/genética , Adolescente , Adulto , Animais , Proteína Morfogenética Óssea 4/genética , Células COS , Chlorocebus aethiops , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Humanos , Fator de Transcrição MSX1/genética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Fator de Transcrição PAX9/química , Fator de Transcrição PAX9/fisiologia , Linhagem , Estrutura Terciária de Proteína
16.
Arch Oral Biol ; 84: 100-105, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28965043

RESUMO

INTRODUCTION: An extended family presenting with several members affected by developmentally missing teeth was investigated by analysis of the MSX1 and PAX9 genes. MATERIALS AND METHODS: Saliva samples were collected and DNA extracted. Primers were designed to span the exons and intron-exon junctions of the MSX1 and PAX9 genes. These primers were optimised using gradient Polymerase Chain Reaction. The amplified fragments were sent for Sanger sequencing RESULTS: a novel heterozygote missense mutation in exon 3 of PAX9 (c.296G > C, p.A99P), was found in two severely affected members of the family as well as a potentially pathogenic heterozygote variant (c.119C > G, p.A40G) in exon 1 of the MSX1 gene. CONCLUSION: The PAX9 A99P mutation is in the DNA binding domain and is predicted to be pathogenic.


Assuntos
Anodontia/genética , Mutação de Sentido Incorreto/genética , Fator de Transcrição PAX9/genética , Anodontia/diagnóstico por imagem , Criança , Eletroforese em Gel de Ágar , Éxons , Feminino , Humanos , Íntrons , Fator de Transcrição MSX1/genética , Masculino , Malta , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Radiografia Panorâmica
17.
J Dent Res ; 96(11): 1282-1289, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28813171

RESUMO

To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well-being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9-/- mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9-/- embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/Edar pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and Edar-related genes are expressed in normal palatal tissues and that the Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/Edar signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex.


Assuntos
Anticorpos Monoclonais/farmacologia , Fissura Palatina/tratamento farmacológico , Fissura Palatina/embriologia , Receptor Edar/agonistas , Fator de Transcrição PAX9/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Hibridização In Situ , Camundongos , Camundongos Endogâmicos , Morfogênese , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
18.
Gene ; 635: 69-76, 2017 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-28847717

RESUMO

Several studies on experimental animals indicate that the process of organogenesis crucially depends upon the spatiotemporal dose of certain critical bio-molecules. Tooth development is also not an exception. While most of the knowledge regarding the molecular mechanism of tooth development comes from the studies on mouse model, pathogenic variations identified in human tooth agenesis also provide valuable information on mammalian tooth development. Until now five major candidate genes have been identified for tooth agenesis in human. Among them, PAX9 plays the crucial role in tooth development and in non-syndromic congenital tooth agenesis. In this study, microsatellite and SNP based genotyping identifies a disease specific haplotype block, which includes PAX9 gene, segregates with autosomal dominant tooth agenesis phenotype. Direct sequencing of PAX9 identifies a novel heterozygous G to A transition at the third base (c.3G>A) of initiation codon leading to ATG to ATA shift in all affected individuals which is absent in all unaffected relatives and 200 control chromosomes. Further, in vitro functional analysis creating PAX9 minigene construct did apparently show no effect on the splice-site migration. It is therefore proposed that haploinsufficiency of PAX9 is the causal factor for tooth agenesis in this family.


Assuntos
Anodontia/genética , Predisposição Genética para Doença , Fator de Transcrição PAX9/genética , Dente/crescimento & desenvolvimento , Animais , Anodontia/fisiopatologia , Genótipo , Haplótipos , Humanos , Camundongos , Mutação , Organogênese/genética , Polimorfismo de Nucleotídeo Único , Dente/fisiopatologia
19.
Clin Epigenetics ; 9: 57, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28572861

RESUMO

BACKGROUND: In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made to examine and integrate the global DNA methylation changes with gene expression profile and their impact on clinical outcome in early stage CLL patients. RESULTS: The integration of DNA methylation profile (n = 14) with the gene expression profile (n = 21) revealed 142 genes as hypermethylated-downregulated and; 62 genes as hypomethylated-upregulated in early stage CLL patients compared to CD19+ B-cells from healthy individuals. The mRNA expression levels of 17 genes identified to be differentially methylated and/or differentially expressed was further examined in early stage CLL patients (n = 93) by quantitative real time PCR (RQ-PCR). Significant differences were observed in the mRNA expression of MEIS1, PMEPA1, SOX7, SPRY1, CDK6, TBX2, and SPRY2 genes in CLL cells as compared to B-cells from healthy individuals. The analysis in the IGHV mutation based categories (Unmutated = 39, Mutated = 54) revealed significantly higher mRNA expression of CRY1 and PAX9 genes in the IGHV unmutated subgroup (p < 0.001). The relative risk of treatment initiation was significantly higher among patients with high expression of CRY1 (RR = 1.91, p = 0.005) or PAX9 (RR = 1.87, p = 0.001). High expression of CRY1 (HR: 3.53, p < 0.001) or PAX9 (HR: 3.14, p < 0.001) gene was significantly associated with shorter time to first treatment. The high expression of PAX9 gene (HR: 3.29, 95% CI 1.172-9.272, p = 0.016) was also predictive of shorter overall survival in CLL. CONCLUSIONS: The DNA methylation changes associated with mRNA expression of CRY1 and PAX9 genes allow risk stratification of early stage CLL patients. This comprehensive analysis supports the concept that the epigenetic changes along with the altered expression of genes have the potential to predict clinical outcome in early stage CLL patients.


Assuntos
Criptocromos/genética , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Leucemia Linfocítica Crônica de Células B/genética , Fator de Transcrição PAX9/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Metilação de DNA , Epigênese Genética , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Regulação para Cima
20.
Mol Med Rep ; 16(1): 806-816, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28560390

RESUMO

Abnormal paired box 9 (PAX9) expression is associated with tumorigenesis, cancer development, invasion and metastasis. The present study investigated the prognostic significance of PAX9 in esophageal squamous cell carcinoma (ESCC) and its role in predicting radiation sensitivity. A total of 52.8% (121/229) ESCC tissues were positive for PAX9. The 1­, 3­ and 5­year disease­free survival (DFS) rates were 72.2, 35.2 and 5.6%, respectively, and the overall survival (OS) rates were and 86.1, 44.4, and 23.1%, respectively, in PAX9­positive tumors. In PAX9­negative tumors, the one­, three­ and five­year DFS rates were 76.9, 47.9 and 24.0%, and the OS rates were 90.9, 57.9 and 38.8%, respectively. Univariate analysis revealed that PAX9, differentiation, T stage, lymph node metastasis, and tumor­node­metastasis stage were associated with OS. Multivariate analysis of DFS and OS revealed that the hazard ratios for PAX9 were 0.624 (95% CI: 0.472­0.869, P=0.004) and 0.673 (95% CI: 0.491­0.922, P=0.014), respectively. Patients that received adjuvant therapy exhibited significant differences in the 5­year DFS (P<0.001) and OS (P<0.001). PAX9­positive ESCC patients who received post­surgery radiotherapy had a significantly greater 5­year DFS (P=0.011) and OS (P=0.009) than patients who received surgery only. Thus, PAX9 may be an independent prognostic factor for the surgical treatment of ESCC and a possible predictor of radiation sensitivity.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Fator de Transcrição PAX9/genética , Tolerância a Radiação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Quimiorradioterapia , Terapia Combinada , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago , Feminino , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Fator de Transcrição PAX9/metabolismo , Prognóstico
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