Dataset Information

Missense Pathogenic variants in KIF4A Affect Dental Morphogenesis Resulting in X-linked Taurodontism, Microdontia and Dens-Invaginatus.

ABSTRACT: The etiology of dental anomalies is multifactorial; and genetic and environmental factors that affect the dental lamina have been implicated. We investigated two families of European ancestry in which males were affected by taurodontism, microdontia and dens invaginatus. In both families, males were related to each other via unaffected females. A linkage analysis was conducted in a New Zealand family, followed by exome sequencing and focused analysis of the X-chromosome. In a US family, exome sequencing of the X-chromosome was followed by Sanger sequencing to conduct segregation analyses. We identified two independent missense variants in KIF4A that segregate in affected males and female carriers. The variant in a New Zealand family (p.Asp371His) predicts the substitution of a residue in the motor domain of the protein while the one in a US family (p.Arg771Lys) predicts the substitution of a residue in the domain that interacts with Protein Regulator of Cytokinesis 1 (PRC1). We demonstrated that the gene is expressed in the developing tooth bud during development, and that the p.Arg771Lys variant influences cell migration in an in vitro assay. These data implicate missense variations in KIF4A in a pathogenic mechanism that causes taurodontism, microdontia and dens invaginatus phenotypes.

SUBMITTER: Gowans LJJ

PROVIDER: S-EPMC6764483 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

<i>Missense Pathogenic variants in KIF4A</i> Affect Dental Morphogenesis Resulting in X-linked Taurodontism, Microdontia and Dens-Invaginatus.

Gowans Lord J J LJJ Cameron-Christie Sophia S Slayton Rebecca L RL Busch Tamara T Romero-Bustillos Miguel M Eliason Steven S Sweat Mason M Sobreira Nara N Yu Wenjie W Kantaputra Piranit N PN Wohler Elizabeth E Adeyemo Wasiu Lanre WL Lachke Salil A SA Anand Deepti D Campbell Collen C Drummond Bernadette K BK Markie David M DM van Vuuren W Jansen WJ van Vuuren L Jansen LJ Casamassimo Paul S PS Ettinger Ronald R Owais Arwa A van Staden I I Amendt Brad A BA Adeyemo Adebowale A AA Murray Jeffrey C JC Robertson Stephen P SP Butali Azeez A

Frontiers in genetics 20190920

The etiology of dental anomalies is multifactorial; and genetic and environmental factors that affect the dental lamina have been implicated. We investigated two families of European ancestry in which males were affected by taurodontism, microdontia and dens invaginatus. In both families, males were related to each other <i>via</i> unaffected females. A linkage analysis was conducted in a New Zealand family, followed by exome sequencing and focused analysis of the X-chromosome. In a US family, e ...[more]

PMID: 31616463

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Project description:Missense variants are present amongst the healthy population, but some of them are causative of human diseases. A classification of variants associated with "healthy" or "diseased" states is therefore not always straightforward. A deeper understanding of the nature of missense variants in health and disease, the cellular processes they may affect, and the general molecular principles which underlie these differences is essential to offer mechanistic explanations of the true impact of pathogenic variants. Here, we have formalised a statistical framework which enables robust probabilistic quantification of variant enrichment across full-length proteins, their domains, and 3D structure-defined regions. Using this framework, we validate and extend previously reported trends of variant enrichment in different protein structural regions (surface/core/interface). By examining the association of variant enrichment with available functional pathways and transcriptomic and proteomic (protein half-life, thermal stability, abundance) data, we have mined a rich set of molecular features which distinguish between pathogenic and population variants: Pathogenic variants mainly affect proteins involved in cell proliferation and nucleotide processing and are enriched in more abundant proteins. Additionally, rare population variants display features closer to common than pathogenic variants. We validate the association between these molecular features and variant pathogenicity by comparing against existing in silico variant impact annotations. This study provides molecular details into how different proteins exhibit resilience and/or sensitivity towards missense variants and provides the rationale to prioritise variant-enriched proteins and protein domains for therapeutic targeting and development. The ZoomVar database, which we created for this study, is available at fraternalilab.kcl.ac.uk/ZoomVar. It allows users to programmatically annotate missense variants with protein structural information and to calculate variant enrichment in different protein structural regions.

Dataset Information

Missense Pathogenic variants in KIF4A Affect Dental Morphogenesis Resulting in X-linked Taurodontism, Microdontia and Dens-Invaginatus.

Publications

<i>Missense Pathogenic variants in KIF4A</i> Affect Dental Morphogenesis Resulting in X-linked Taurodontism, Microdontia and Dens-Invaginatus.

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