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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00800

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

 Lord Gowans1,  Sophia Cameron-Christie2*,  Rebecca Slayton3, Tamara Busch4,  M Romero-Bustillos4, Steven Eliason4, Mason Sweat4, Nara Sobreira5, Wenjie Yu4, Piranit N. Kantaputra6,  Elizabeth Wohler7,  Wasiu L. Adeyemo8, Salil A. Lachke9, Deepti Anand9, Collen Campbell4, Bernadette Drummond10, DM Markie10, W A. Jansen van Vuuren11, L Jansen van Vuuren11, Paul Casamassimo12, Ronald Ettinger4, Arwa Owais4, IP van Staden13,  Brad A. Amendt4,  Adebowale Adeyemo14,  Jeffrey C. Murray4,  Stephen Robertson15 and  Azeez Butali4*
  • 1Kwame Nkrumah University of Science and Technology, Ghana
  • 2University of Otago, New Zealand
  • 3University of Washington, United States
  • 4The University of Iowa, United States
  • 5Johns Hopkins University, United States
  • 6Chiang Mai University, Thailand
  • 7The Johns Hopkins Hospital, Johns Hopkins Medicine, United States
  • 8University of Lagos, Nigeria
  • 9University of Delaware, United States
  • 10University of Otago, Christchurch, New Zealand
  • 11the Sir John Walsh Research Institute, University of Otago, New Zealand
  • 12The Ohio State University, United States
  • 13Other, New Zealand
  • 14National Institutes of Health (NIH), United States
  • 15Department of Women’s and Children’s Health, University of Otago, New Zealand

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 the New Zealand family, followed by exome sequencing and focused analysis of the X-chromosome. In the 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.

Keywords: exome sequencing, Microdontia, Taurodontism, dens invaginatus, X-linked recessive

Received: 17 Dec 2018; Accepted: 30 Jul 2019.

Edited by:

Enrico Baruffini, University of Parma, Italy

Reviewed by:

Ana C. Acevedo, University of Brasilia, Brazil
Ricardo D. Coletta, Campinas State University, Brazil  

Copyright: © 2019 Gowans, Cameron-Christie, Slayton, Busch, Romero-Bustillos, Eliason, Sweat, Sobreira, Yu, Kantaputra, Wohler, Adeyemo, Lachke, Anand, Campbell, Drummond, Markie, Jansen van Vuuren, Jansen van Vuuren, Casamassimo, Ettinger, Owais, van Staden, Amendt, Adeyemo, Murray, Robertson and Butali. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Sophia Cameron-Christie, University of Otago, Dunedin, 9016, Otago, New Zealand,
Prof. Azeez Butali, The University of Iowa, Iowa City, United States,