10.3389/fgene.2019.00800.s007 Lord J.J. Gowans Lord J.J. Gowans Sophia Cameron-Christie Sophia Cameron-Christie Rebecca L. Slayton Rebecca L. Slayton Tamara Busch Tamara Busch Miguel Romero-Bustillos Miguel Romero-Bustillos Steven Eliason Steven Eliason Mason Sweat Mason Sweat Nara Sobreira Nara Sobreira Wenjie Yu Wenjie Yu Piranit N. Kantaputra Piranit N. Kantaputra Elizabeth Wohler Elizabeth Wohler Wasiu Lanre Adeyemo Wasiu Lanre Adeyemo Salil A. Lachke Salil A. Lachke Deepti Anand Deepti Anand Collen Campbell Collen Campbell Bernadette K. Drummond Bernadette K. Drummond David M. Markie David M. Markie W. Jansen van Vuuren W. Jansen van Vuuren L. Jansen van Vuuren L. Jansen van Vuuren Paul S. Casamassimo Paul S. Casamassimo Ronald Ettinger Ronald Ettinger Arwa Owais Arwa Owais I. van Staden I. van Staden Brad A. Amendt Brad A. Amendt Adebowale A. Adeyemo Adebowale A. Adeyemo Jeffrey C. Murray Jeffrey C. Murray Stephen P. Robertson Stephen P. Robertson Azeez Butali Azeez Butali Image_7_Missense Pathogenic variants in KIF4A Affect Dental Morphogenesis Resulting in X-linked Taurodontism, Microdontia and Dens-Invaginatus.tif Frontiers 2019 exome sequencing X-linked recessive microdontia taurodontism dens invaginatus 2019-09-20 16:11:45 Figure https://frontiersin.figshare.com/articles/figure/Image_7_Missense_Pathogenic_variants_in_KIF4A_Affect_Dental_Morphogenesis_Resulting_in_X-linked_Taurodontism_Microdontia_and_Dens-Invaginatus_tif/9886040 <p>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.</p>