TY - JOUR
T1 - Missense Pathogenic variants in KIF4A Affect Dental Morphogenesis Resulting in X-linked Taurodontism, Microdontia and Dens-Invaginatus
AU - Gowans, Lord J.J.
AU - Cameron-Christie, Sophia
AU - Slayton, Rebecca L.
AU - Busch, Tamara
AU - Romero-Bustillos, Miguel
AU - Eliason, Steven
AU - Sweat, Mason
AU - Sobreira, Nara
AU - Yu, Wenjie
AU - Kantaputra, Piranit N.
AU - Wohler, Elizabeth
AU - Adeyemo, Wasiu Lanre
AU - Lachke, Salil A.
AU - Anand, Deepti
AU - Campbell, Collen
AU - Drummond, Bernadette K.
AU - Markie, David M.
AU - van Vuuren, W. Jansen
AU - van Vuuren, L. Jansen
AU - Casamassimo, Paul S.
AU - Ettinger, Ronald
AU - Owais, Arwa
AU - van Staden, I.
AU - Amendt, Brad A.
AU - Adeyemo, Adebowale A.
AU - Murray, Jeffrey C.
AU - Robertson, Stephen P.
AU - Butali, Azeez
N1 - Publisher Copyright:
© Copyright © 2019 Gowans, Cameron-Christie, Slayton, Busch, Romero-Bustillos, Eliason, Sweat, Sobreira, Yu, Kantaputra, Wohler, Adeyemo, Lachke, Anand, Campbell, Drummond, Markie, van Vuuren, van Vuuren, Casamassimo, Ettinger, Owais, van Staden, Amendt, Adeyemo, Murray, Robertson and Butali.
PY - 2019/9/20
Y1 - 2019/9/20
N2 - 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.
AB - 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.
KW - X-linked recessive
KW - dens invaginatus
KW - exome sequencing
KW - microdontia
KW - taurodontism
UR - http://www.scopus.com/inward/record.url?scp=85073031378&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073031378&partnerID=8YFLogxK
U2 - 10.3389/fgene.2019.00800
DO - 10.3389/fgene.2019.00800
M3 - Article
C2 - 31616463
AN - SCOPUS:85073031378
SN - 1664-8021
VL - 10
JO - Frontiers in Genetics
JF - Frontiers in Genetics
M1 - 800
ER -