Prediction methods have become an integral part of biomedical and biotechnological research. However, their clinical interpretations are largely based on biochemical or molecular data, but not clinical data. Here, we focus on improving the reliability and clinical applicability of prediction algorithms. We assembled and curated two large non-overlapping large databases of clinical phenotypes. These phenotypes were caused by missense variations in 44 and 63 genes associated with Mendelian diseases. We used these databases to establish and validate the model, allowing us to improve the predictions obtained from EVmutation, SNAP2 and PoPMuSiC 2.1. The predictions of clinical effects suffered from a lack of specificity, which appears to be the common constraint of all recently used prediction methods, although predictions mediated by these methods are associated with nearly absolute sensitivity. We introduced evidence-based tailoring of the default settings of the prediction methods; this tailoring substantially improved the prediction outcomes. Additionally, the comparisons of the clinically observed and theoretical variations led to the identification of large previously unreported pools of variations that were under negative selection during molecular evolution. The evolutionary variation analysis approach described here is the first to enable the highly specific identification of likely disease-causing missense variations that have not yet been associated with any clinical phenotype.

• MeSH
• algoritmy MeSH
• ektodysplasiny genetika   MeSH
• fenotyp MeSH
• genetická variace MeSH
• genetické nemoci vrozené genetika   MeSH
• genomika MeSH
• glukosa-6-fosfátdehydrogenasa genetika   MeSH
• hemoglobiny genetika   MeSH
• hepatocytární jaderný faktor 4 genetika   MeSH
• lidé MeSH
• missense mutace MeSH
• modely genetické * MeSH
• molekulární evoluce MeSH
• mutace * MeSH
• pravděpodobnostní funkce MeSH
• proteomika MeSH
• tyrosinfosfatasa nereceptorového typu 11 genetika   MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• EDA protein, human MeSH Prohlížeč
• ektodysplasiny MeSH
• G6PD protein, human MeSH Prohlížeč
• glukosa-6-fosfátdehydrogenasa MeSH
• hemoglobin B MeSH Prohlížeč
• hemoglobiny MeSH
• hepatocytární jaderný faktor 4 MeSH
• HNF4A protein, human MeSH Prohlížeč
• PTPN11 protein, human MeSH Prohlížeč
• tyrosinfosfatasa nereceptorového typu 11 MeSH

The Eda pathway ( Eda, Edar, Edaradd) plays an important role in tooth development, determining tooth number, crown shape, and enamel formation. Here we show that the Eda pathway also plays a key role in root development. Edar (the receptor) is expressed in Hertwig's epithelial root sheath (HERS) during root development, with mutant mice showing a high incidence of taurodontism: large pulp chambers lacking or showing delayed bifurcation or trifurcation of the roots. The mouse upper second molars in the Eda pathway mutants show the highest incidence of taurodontism, this enhanced susceptibility being matched in human patients with mutations in EDA-A1. These taurodont teeth form due to defects in the direction of extension of the HERS from the crown, associated with a more extensive area of proliferation of the neighboring root mesenchyme. In those teeth where the angle at which the HERS extends from the crown is very wide and therefore more vertical, the mutant HERSs fail to reach toward the center of the tooth in the normal furcation region, and taurodont teeth are created. The phenotype is variable, however, with milder changes in angle and proliferation leading to normal or delayed furcation. This is the first analysis of the role of Eda in the root, showing a direct role for this pathway during postnatal mouse development, and it suggests that changes in proliferation and angle of HERS may underlie taurodontism in a range of syndromes.

• Klíčová slova
• ectodermal dysplasia, ectodysplasins, epithelium, furcation defects, periodontium, tooth,
• MeSH
• abnormality zubů genetika   MeSH
• dítě MeSH
• ektodysplasiny genetika   MeSH
• fenotyp MeSH
• kavita zubní dřeně abnormality   MeSH
• lidé MeSH
• mladiství MeSH
• moláry abnormality   embryologie   MeSH
• myši MeSH
• odontogeneze genetika   MeSH
• rentgenová mikrotomografie MeSH
• signální transdukce MeSH
• zubní kořen abnormality   embryologie   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• EDA protein, human MeSH Prohlížeč
• Eda protein, mouse MeSH Prohlížeč
• ektodysplasiny MeSH