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Front Genet. 2019 Sep 20;10:800. doi: 10.3389/fgene.2019.00800. eCollection 2019.

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

Author information

1
Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
2
Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
3
Department of Pediatric Dentistry, University of Washington, Seattle, WA, United States.
4
Department of Oral Pathology, Radiology and Medicine, University of Iowa, Iowa City, IA, United States.
5
Department of Anatomy, University of Iowa, Iowa City, IA, United States.
6
Institute of Genetic Medicine, John Hopkins University, Baltimore, MD, United States.
7
Center of Excellence in Medical Genetics Research, Chiang Mai University, Chiang Mai, Thailand.
8
Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
9
Department of Oral and Maxillofacial Surgery, University of Lagos, Lagos, Nigeria.
10
Department of Biological Sciences, University of Delaware, Newark, DE, United States.
11
Department of Internal Medicine, University of Iowa, Iowa City, IA, United States.
12
Department of Oral Sciences, University of Otago, Dunedin, New Zealand.
13
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
14
Department of Pediatric Dentistry, Ohio State University, Columbus, OH, United States.
15
Department of Prosthodontics, University of Iowa, Iowa City, IA, United States.
16
Department of Pediatric Dentistry, College of Dentistry, University of Iowa, Iowa City, IA, United States.
17
National Human Genomic Research Institute, Bethesda, MD, United States.
18
Department of Pediatrics University of Iowa, Iowa City, IA, United States.

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.

KEYWORDS:

X-linked recessive; dens invaginatus; exome sequencing; microdontia; taurodontism

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