RESUMO
An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.
Assuntos
Evolução Biológica , Receptor Edar/genética , Glândulas Exócrinas/fisiologia , Cabelo/fisiologia , Camundongos , Modelos Animais , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Evolução Molecular , Técnicas de Introdução de Genes , Pleiotropia Genética , Haplótipos , Humanos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Couro Cabeludo/fisiologia , Alinhamento de Sequência , Adulto JovemRESUMO
INTRODUCTION: The interaction between activated hepatic stellate cells (aHSCs) and macrophages is central to liver fibrosis development. The cargo contained within aHSC exosomes (aHSC-EXOs) and how aHSC-EXOs affect macrophage function is poorly understood. METHODS: RNA from aHSC-EXOs was separated into small (<200-basepairs) and large (≥200-basepairs) RNA species, transfected into macrophages, and macrophage IL-6 and TNFα mRNA expression and protein secretion measured. Next generation sequencing was performed on EXOs from rat quiescent and aHSCs and human aHSCs. aHSCs were transfected with siRNA against ectodysplasin-A (EDA), EXOs collected, and their effect on macrophage function analyzed. Human cirrhotic liver was analyzed for EDA mRNA expression and compared to non-tumor liver (NTL). RESULTS: Transfection with large RNA from aHSC-EXOs stimulated macrophage IL-6 and TNFα mRNA expression and protein secretion. EDA mRNA was highly expressed in aHSCs and transfection of aHSCs with EDA-siRNA decreased aHSC-EXO EDA mRNA and blunted the effect of aHSC-EXOs on macrophage function (IL-6/TNFα expression and macrophage migration). Human cirrhotic liver exhibited high EDA mRNA compared to NTL. CONCLUSIONS: HSC activation leads to altered EXO mRNA/miRNA profiles with aHSC-EXOs mRNAs exerting a dominant role in altering macrophage function. Ectodysplasin-A mRNA is an important component in aHSC-EXOs in regulating macrophage function.
Assuntos
Exossomos , Neoplasias Hepáticas , Animais , Ectodisplasinas/metabolismo , Ectodisplasinas/farmacologia , Receptor Edar , Exossomos/metabolismo , Células Estreladas do Fígado/metabolismo , Humanos , Interleucina-6/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Macrófagos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that broad activation of Edar expression precedes its spatial restriction to tooth signaling centers. This reveals a hidden two-step patterning process for tooth signaling centers, which was modeled with a single activator-inhibitor pair subject to reaction-diffusion (RD). The study of Edar expression also unveiled successive phases of signaling center formation, erasing, recovering, and fusion. Our model, in which R2 signaling center is not intrinsically defective but erased by the broad activation preceding M1 signaling center formation, predicted the surprising rescue of R2 in Edar mutant mice, where activation is reduced. The importance of this R2-M1 interaction was confirmed by ex vivo cultures showing that R2 is capable of forming a tooth. Finally, by introducing chemotaxis as a secondary process to RD, we recapitulated in silico different conditions in which R2 and M1 centers fuse or not. In conclusion, pattern formation in the mouse molar field relies on basic mechanisms whose dynamics produce embryonic patterns that are plastic objects rather than fixed end points.
Assuntos
Padronização Corporal , Receptor Edar/metabolismo , Modelos Biológicos , Transdução de Sinais , Dente/embriologia , Dente/metabolismo , Animais , Quimiotaxia , Receptor Edar/genética , Epitélio/embriologia , Epitélio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Cabelo/embriologia , Camundongos , Camundongos Mutantes , Germe de Dente/embriologia , Germe de Dente/metabolismoRESUMO
Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.
Assuntos
Padronização Corporal , Plumas/citologia , Plumas/embriologia , Transdução de Sinais , Animais , Fenômenos Biomecânicos , Aves/embriologia , Agregação Celular , Contagem de Células , Movimento Celular , Forma Celular , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Voo Animal/fisiologia , Mesoderma/citologia , Mesoderma/embriologia , Pele/citologia , Pele/embriologia , beta Catenina/metabolismoRESUMO
Most current methods for detecting natural selection from DNA sequence data are limited in that they are either based on summary statistics or a composite likelihood, and as a consequence, do not make full use of the information available in DNA sequence data. We here present a new importance sampling approach for approximating the full likelihood function for the selection coefficient. Our method CLUES treats the ancestral recombination graph (ARG) as a latent variable that is integrated out using previously published Markov Chain Monte Carlo (MCMC) methods. The method can be used for detecting selection, estimating selection coefficients, testing models of changes in the strength of selection, estimating the time of the start of a selective sweep, and for inferring the allele frequency trajectory of a selected or neutral allele. We perform extensive simulations to evaluate the method and show that it uniformly improves power to detect selection compared to current popular methods such as nSL and SDS, and can provide reliable inferences of allele frequency trajectories under many conditions. We also explore the potential of our method to detect extremely recent changes in the strength of selection. We use the method to infer the past allele frequency trajectory for a lactase persistence SNP (MCM6) in Europeans. We also infer the trajectory of a SNP (EDAR) in Han Chinese, finding evidence that this allele's age is much older than previously claimed. We also study a set of 11 pigmentation-associated variants. Several genes show evidence of strong selection particularly within the last 5,000 years, including ASIP, KITLG, and TYR. However, selection on OCA2/HERC2 seems to be much older and, in contrast to previous claims, we find no evidence of selection on TYRP1.
Assuntos
Frequência do Gene/genética , Análise de Sequência de DNA/métodos , Alelos , Povo Asiático/genética , Sequência de Bases/genética , DNA/genética , Receptor Edar/genética , Haplótipos/genética , Humanos , Funções Verossimilhança , Cadeias de Markov , Componente 6 do Complexo de Manutenção de Minicromossomo/genética , Modelos Genéticos , Método de Monte Carlo , Pigmentação/genética , População Branca/genéticaRESUMO
Because of the ubiquitous adaptability of our material culture, some human populations have occupied extreme environments that intensified selection on existing genomic variation. By 32,000 years ago, people were living in Arctic Beringia, and during the Last Glacial Maximum (LGM; 28,000-18,000 y ago), they likely persisted in the Beringian refugium. Such high latitudes provide only very low levels of UV radiation, and can thereby lead to dangerously low levels of biosynthesized vitamin D. The physiological effects of vitamin D deficiency range from reduced dietary absorption of calcium to a compromised immune system and modified adipose tissue function. The ectodysplasin A receptor (EDAR) gene has a range of pleiotropic effects, including sweat gland density, incisor shoveling, and mammary gland ductal branching. The frequency of the human-specific EDAR V370A allele appears to be uniquely elevated in North and East Asian and New World populations due to a bout of positive selection likely to have occurred circa 20,000 y ago. The dental pleiotropic effects of this allele suggest an even higher occurrence among indigenous people in the Western Hemisphere before European colonization. We hypothesize that selection on EDAR V370A occurred in the Beringian refugium because it increases mammary ductal branching, and thereby may amplify the transfer of critical nutrients in vitamin D-deficient conditions to infants via mothers' milk. This hypothesized selective context for EDAR V370A was likely intertwined with selection on the fatty acid desaturase (FADS) gene cluster because it is known to modulate lipid profiles transmitted to milk from a vitamin D-rich diet high in omega-3 fatty acids.
Assuntos
Clima Frio , Receptor Edar , Ácidos Graxos/metabolismo , Troca Materno-Fetal/fisiologia , Leite Humano/metabolismo , Seleção Genética/fisiologia , Vitamina D/metabolismo , Alelos , Receptor Edar/genética , Receptor Edar/metabolismo , Feminino , Humanos , Masculino , Glândulas Mamárias Humanas/anatomia & histologia , Glândulas Mamárias Humanas/metabolismo , GravidezRESUMO
Ectodysplasin A (Eda) signaling activates NF-κB during skin appendage formation, but how Eda controls specific gene transcription remains unclear. Here, we find that Eda triggers the formation of an NF-κB-associated SWI/SNF (BAF) complex in which p50/RelB recruits a linker protein, Tfg, that interacts with BAF45d in the BAF complex. We further reveal that Tfg is initially induced by Eda-mediated RelB activation and then bridges RelB and BAF for subsequent gene regulation. The BAF component BAF250a is particularly up-regulated in skin appendages, and epidermal knockout of BAF250a impairs skin appendage development, resulting in phenotypes similar to those of Eda-deficient mouse models. Transcription profiling identifies several target genes regulated by Eda, RelB, and BAF. Notably, RelB and the BAF complex are indispensable for transcription of Eda target genes, and both BAF complex and Eda signaling are required to open chromatin of Eda targets. Our studies thus suggest that Eda initiates a signaling cascade and recruits a BAF complex to specific gene loci to facilitate transcription during organogenesis.
Assuntos
Proteínas Cromossômicas não Histona/fisiologia , Ectodisplasinas/metabolismo , Organogênese/genética , Pele/embriologia , Fator de Transcrição RelB/genética , Fatores de Transcrição/fisiologia , Transcrição Gênica/fisiologia , Animais , Cromatina/metabolismo , Ectodisplasinas/genética , Receptor Edar/genética , Receptor Edar/metabolismo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Proteínas/genética , Proteínas/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/fisiologia , Fator de Transcrição RelB/metabolismo , Ativação Transcricional/fisiologia , Regulação para CimaRESUMO
In hair follicle development, a placode-derived signal is believed to induce formation of the dermal condensation, an essential component of ectodermal organs. However, the identity of this signal is unknown. Furthermore, although induction and patterning of hair follicles are intimately linked, it is not known whether the mesenchymal condensation is necessary for inducing the initial epithelial pattern. Here, we show that fibroblast growth factor 20 (Fgf20) is expressed in hair placodes and is induced by and functions downstream from epithelial ectodysplasin (Eda)/Edar and Wnt/ß-Catenin signaling to initiate formation of the underlying dermal condensation. Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles and subsequent formation of guard, awl, and auchene hairs. Although primary dermal condensations are absent in Fgf20 mutant mice, a regular array of hair placodes is formed, demonstrating that the epithelial patterning process is independent of known histological and molecular markers of underlying mesenchymal patterns during the initial stages of hair follicle development.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Folículo Piloso/embriologia , Animais , Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Camundongos , Transdução de Sinais , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
Nonsyndromic oligodontia is a rare congenital anomaly. Mutations in the ectodysplasin A receptor (EDAR) gene are the primary cause of hypohidrotic ectodermal dysplasia but are rarely reported in nonsyndromic oligodontia. This study investigated EDAR mutations in multiplex nonsyndromic oligodontia and comparatively analyzed the EDAR- and EDA-related tooth agenesis patterns. Mutation screening was carried out using whole-exome sequencing and familial segregation. Evolutionary conservation and conformational analyses were used to evaluate the potential pathogenic influence of EDAR mutants. EDAR mutations were found to occur in 10.7% of nonsyndromic oligodontia cases. We reported seven heterozygous mutations of EDAR, including five novel mutations (c.404G>A, c.871G>A, c.43G>A, c.1072C>T, and c.1109T>C) and two known mutations (c.319A>G and c.1138A>C). Genotype-phenotype correlation analysis demonstrated that the EDAR-related tooth agenesis pattern was markedly different from EDA. The mandibular second premolars were most frequently missing (57.69%) in EDAR-mutated patients. Our results provide new evidence for the genotypic study of nonsyndromic oligodontia and suggest that EDAR haploinsufficiency results in nonsyndromic tooth agenesis. Furthermore, the distinct pattern between EDAR- and EDA-related tooth agenesis can be used as a guide for mutation screening during the clinical genetic diagnosis of this genetic disorder.
Assuntos
Anodontia/genética , Receptor Edar/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Mutação , Sequenciamento do Exoma , Adulto JovemRESUMO
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 JovemRESUMO
Tooth morphogenesis is initiated by reciprocal interactions between the ectoderm and neural crest-derived mesenchyme. During tooth development, tooth cusps are regulated by precise control of proliferation of cell clusters, termed enamel knots, that are present among dental epithelial cells. The interaction of ectodysplasin-A (EDA) with its receptor, EDAR, plays a critical role in cusp formation by these enamel knots, and mutations of these genes is a cause of ectodermal dysplasia. It has also been reported that deficiency in Nkx2-3, encoding a member of the NK2 homeobox family of transcription factors, leads to cusp absence in affected teeth. However, the molecular role of NKX2-3 in tooth morphogenesis is not clearly understood. Using gene microarray analysis in mouse embryos, we found that Nkx2-3 is highly expressed during tooth development and increased during the tooth morphogenesis, especially during cusp formation. We also demonstrate that NKX2-3 is a target molecule of EDA and critical for expression of the cell cycle regulator p21 in the enamel knot. Moreover, NKX2-3 activated the bone morphogenetic protein (BMP) signaling pathway by up-regulating expression levels of Bmp2 and Bmpr2 in dental epithelium and decreased the expression of the dental epithelial stem cell marker SRY box 2 (SOX2). Together, our results indicate that EDA/NKX2-3 signaling is essential for enamel knot formation during tooth morphogenesis in mice.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Esmalte Dentário/metabolismo , Ectodisplasinas/metabolismo , Proteínas de Homeodomínio/fisiologia , Odontogênese/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , Animais , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Esmalte Dentário/citologia , Receptor Edar , Células Epiteliais/metabolismo , Feminino , Genes Homeobox , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Knockout , Morfogênese , Odontogênese/genética , Técnicas de Cultura de Órgãos , Gravidez , Regiões Promotoras Genéticas , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a rare congenital disorder arising from the abnormal development of ectoderm derived structures, including skin, hair, nails, teeth and glands. These patients have sparse hair on the whole body, including the scalp, as well as hypoplastic teeth. They have no resistance to heat as a result of abnormal sweat glands. In total, four genes, namely ectodysplasin A (EDA), ectodysplasin A receptor (EDAR), EDAR-associated death domain protein (EDARADD) and Wnt family member 10A (WNT10A), are known to be involved in the etiology of HED. METHODS: In the present study, we investigated two consanguineous Kashmiri families (A &B) with an autosomal recessive form of HED. Using whole exome sequencing and different bioinformatics tools, we detected a recurrent mutation causing severe HED. RESULTS: We identified an already known rare homozygous missense (NM_022336 c.1300 T>C; p.W434R; minor allele frequency 0.00007) variant in exon 12 of the EDAR gene. This variant segregated with a homozygous form in all patients and their obligate carriers were heterozygous. A panel of > 100 unrelated ethnically matched controls was screened, and the mutation was not identified outside the families. Furthermore, the candidate variant is predicted to be damaging by in silico software giving a CADD (Combined Annotation Dependent Depletion) score of 25.5, which indicates that the variant is among the top 1% of the deleterious variants in the human genome. CONCLUSIONS: The identification of the same homozygous mutation segregating with disease in two different families supports the important role of the gene in the development of the disorder and this may contribute to novel approaches, prenatal diagnosis and genetic counseling of families with EDAR related disorders.
Assuntos
Consanguinidade , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Displasia Ectodérmica Anidrótica Tipo 1/genética , Receptor Edar/genética , Genes Recessivos , Mutação de Sentido Incorreto , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Sequenciamento do ExomaRESUMO
Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate.
Assuntos
Displasia Ectodérmica/genética , Ectodisplasinas/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Mutação , Análise de Sequência de DNA/métodos , Proteínas Wnt/genética , Consanguinidade , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , TurquiaRESUMO
Hypohidrotic ectodermal dysplasia (HED) is a rare genetic condition resulting from defective development of ectodermal derivatives, such as hair, teeth, and sweat glands. Autosomal recessive (AR) forms of HED may be caused by pathogenic variants of the ectodysplasin A1 receptor (EDAR) gene that encodes a receptor involved in the NF-κB signaling pathway. Here, we describe three cases of AR-HED in families of Turkish, Austrian, and German-American origin (with or without known consanguinity). In these cases, two out-of-frame deletions and a pathogenic missense variant of EDAR were found to be disease-causing due to reduced availability of the respective messenger RNA or impaired interaction of the encoded protein with its binding partner leading to diminished signal transduction. The same missense variant, c.1258C>T (p.Arg420Trp), has actually been reported to be restricted to the Icelandic population and to be associated with non-syndromic tooth agenesis but not HED. As our patient has no known relationship to Icelandic individuals and displays a rather severe HED phenotype, we suggest that EDAR-Arg420Trp is a more widespread variant, possibly with variable clinical expressivity.
Assuntos
Displasia Ectodérmica Hipo-Hidrótica Autossômica Recessiva/diagnóstico , Displasia Ectodérmica Hipo-Hidrótica Autossômica Recessiva/genética , Receptor Edar/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Mutação , Adulto , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Linhagem , Fenótipo , RadiografiaRESUMO
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 , Citocinas , 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/genéticaRESUMO
The dental abnormalities are the typical features of many ectodermal dysplasias along with congenital malformations of nails, skin, hair, and sweat glands. However, several reports of non-syndromic/isolated tooth agenesis have also been found in the literature. The characteristic features of hypohidrotic ectodermal dysplasia (HED) comprise of hypodontia/oligodontia, along with hypohidrosis/anhidrosis, and hypotrichosis. Pathogenic variants in EDA, EDAR, EDARADD, and TRAF6, cause the phenotypic expression of HED. Genetic alterations in EDA and WNT10A cause particularly non-syndromic/isolated oligodontia. In the current project, we recruited 57 patients of 17 genetic pedigrees (A-Q) from different geographic regions of the world, including Pakistan, Egypt, Saudi Arabia, and Syria. The molecular investigation of different syndromic and non-syndromic dental conditions, including hypodontia, oligodontia, generalized odontodysplasia, and dental crowding was carried out by using exome and Sanger sequencing. We have identified a novel missense variant (c.311G>A; p.Arg104His) in WNT10A in three oligodontia patients of family A, two novel sequence variants (c.207delinsTT, p.Gly70Trpfs*25 and c.1300T>G; p.Try434Gly) in EDAR in three patients of family B and four patients of family C, respectively. To better understand the structural and functional consequences of missense variants in WNT10A and EDAR on the stability of the proteins, we have performed extensive molecular dynamic (MD) simulations. We have also identified three previously reported pathogenic variants (c.1076T>C; p.Met359Thr), (c.1133C>T; p.Thr378Met) and (c.594_595insC; Gly201Argfs*39) in EDA in family D (four patients), E (two patients) and F (one patient), correspondingly. Presently, our data explain the genetic cause of 18 syndromic and non-syndromic tooth agenesis patients in six autosomal recessive and X-linked pedigrees (A-F), which expand the mutational spectrum of these unique clinical manifestations.
Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/patologia , Ectodisplasinas/genética , Receptor Edar/genética , Simulação de Dinâmica Molecular , Proteínas Wnt/genética , Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/química , Ectodisplasinas/metabolismo , Receptor Edar/química , Receptor Edar/metabolismo , Humanos , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Estabilidade Proteica , Estrutura Terciária de Proteína , Sequenciamento do Exoma , Proteínas Wnt/química , Proteínas Wnt/metabolismoRESUMO
Hypohidrotic ectodermal dysplasia (HED) results from mutation of the EDA, EDAR or EDARADD genes and is characterized by reduced or absent eccrine sweat glands, hair follicles and teeth, and defective formation of salivary, mammary and craniofacial glands. Mouse models with HED also carry Eda, Edar or Edaradd mutations and have defects that map to the same structures. Patients with HED have ear, nose and throat disease, but this has not been investigated in mice bearing comparable genetic mutations. We report that otitis media, rhinitis and nasopharyngitis occur at high frequency in Eda and Edar mutant mice and explore the pathogenic mechanisms related to glandular function, microbial and immune parameters in these lines. Nasopharynx auditory tube glands fail to develop in HED mutant mice and the functional implications include loss of lysozyme secretion, reduced mucociliary clearance and overgrowth of nasal commensal bacteria accompanied by neutrophil exudation. Heavy nasopharynx foreign body load and loss of gland protection alters the auditory tube gating function and the auditory tubes can become pathologically dilated. Accumulation of large foreign body particles in the bulla stimulates granuloma formation. Analysis of immune cell populations and myeloid cell function shows no evidence of overt immune deficiency in HED mutant mice. Our findings using HED mutant mice as a model for the human condition support the idea that ear and nose pathology in HED patients arises as a result of nasal and nasopharyngeal gland deficits, reduced mucociliary clearance and impaired auditory tube gating function underlies the pathological sequelae in the bulla.
Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Animais , Modelos Animais de Doenças , Orelha Média/patologia , Displasia Ectodérmica Anidrótica Tipo 1/fisiopatologia , Predisposição Genética para Doença , Humanos , Camundongos , Muramidase/genética , Muramidase/metabolismo , Mutação , NF-kappa B/genética , Nariz/patologia , FenótipoRESUMO
Ectodysplasin (Eda) is the most studied tumor necrosis ligand in the field of developmental biology. In all vertebrates studied so far, inactivating germline mutations in Eda lead to the genetic disease called hypohidrotic ectodermal dysplasia (HED). In humans, HED is a life-threatening condition in particular in infants due to absent or severely reduced sweating leading to hyperthermia. HED is also characterized by sparse hair, and oligo- or anodontia. Research of the Eda pathway has not only increased our knowledge on ectodermal appendage development and etiology of developmental disorders, but also on evolution of several vertebrate species including humankind. Studies on mouse and dog models of HED has led to one of the most stunning breakthroughs in applied developmental biology research by showing that a short-term treatment of neonates with a synthetic ligand corrects many of the HED-associated traits. Eighteen years after the identification of EDA as the causative gene in HED, a phase II trial aiming at permanent correction of the disease is now ongoing. This review summarizes the latest discoveries in the Eda field and points to areas that need further investigation such as the possible involvement of Eda in cell migration, stem cell maintenance, or cancer.
Assuntos
Ectodisplasinas/metabolismo , Receptor Edar/metabolismo , Animais , Displasia Ectodérmica Anidrótica Tipo 1/genética , Displasia Ectodérmica Anidrótica Tipo 1/metabolismo , Ectodisplasinas/genética , Humanos , Transdução de SinaisRESUMO
The ectodysplasinA receptor gene (EDAR) plays an important role in the development of ectoderm. The derived G allele of its key missense variant EDARV370A is prevalent in East Asians and Americans, but rare in Africans and Europeans. This leads to distinct ectodermal-derived phenotypes between different continental groups, such as the straighter and thicker hair, more eccrine sweat glands, feminine smaller breasts, shovel incisors characteristic of East Asians. At present, we know little about the association between EDARV370A and facial and ear morphology characteristics. To better understand the effect of EDARV370A on craniofacial phenotypes, we systematically examined the association between EDARV370A and 136 facial quantitative phenotypes, one chin ordinal phenotype and six ear ordinal phenotypes in 715 Uyghurs. The quantitative phenotypes were derived by applying our automated landmark annotation method to facial 3D photos and the ordinal phenotypes were manually graded from facial 2D photos. The analysis identified significant association (P<0.05 after multiple testing correction) between EDARV370A and eight facial phenotypes, one chin phenotype and three ear morphology phenotypes. Our study thus elucidated the pleotropic effect of EDARV370A on craniofacial phenotypes in a European-Asian admixed Uyghur population.
Assuntos
Povo Asiático/genética , Orelha/anatomia & histologia , Receptor Edar/genética , Face/anatomia & histologia , Mutação de Sentido Incorreto , Adolescente , Adulto , Alelos , Povo Asiático/etnologia , China/etnologia , Orelha/crescimento & desenvolvimento , Receptor Edar/metabolismo , Feminino , Humanos , Masculino , Desenvolvimento Maxilofacial , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
Hair and teeth are appendages of ectodermal origin, and there are common molecular backgrounds involved in their formation. To date, it has been revealed that a non-synonymous polymorphism in EDAR has effects on the morphological variation in both hair and teeth. Previous association studies have confirmed that single-nucleotide polymorphisms (SNPs) in/near THADA, FRAS1, WNT10A, NAF1 and FGFR2 are associated with hair morphology. In this study, we thus examined whether these SNPs are also associated with dental characteristics. We measured metric dental traits including crown size and also evaluated non-metric dental traits using plaster casts obtained from subjects (272 Japanese and 226 Koreans). DNA samples were prepared from the subjects and genotyped for the hair morphology-associated SNPs. We observed a significant association of crown size with an SNP in WNT10A (rs7349332), but not with SNPs in other genes. Therefore, we further examined four SNPs within and around WNT10A, among which rs10177996 had the strongest association with dental traits. World distribution of the derived allele in rs10177996, which is associated with larger teeth, showed that Eurasians have a higher allele frequency than Africans. Together with previous studies on hair morphology, this study demonstrated that common variations in WNT10A have pleiotropic effects on the morphology of ectodermal appendages.