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.

Expanding the KIF4A‐associated phenotype

“…(Asp102Asn)) as causative of taurodontism, microdontia, and dens invaginatus in two patients (Gowans et al, 2019; Figure 1).…”

“…The authors proposed KIF4A as a candidate gene for congenital hydrocephalus as an allelic phenotype, also based on the additional functional consideration that KIF4A is a member of the L1CAM recycling pathway and variants in L1CAM are well known to cause X‐linked isolated and syndromic hydrocephalus (Basel‐Vanagaite et al, 2006 ). A recent study of two families attributed a possible role for KIF4A in dental morphogenesis and identified two missense variants (c.2312G>A, p.(Arg771Lys), and c.304G>A, p.(Asp102Asn)) as causative of taurodontism, microdontia, and dens invaginatus in two patients (Gowans et al, 2019 ; Figure 1 ).…”

“…A nuclear localization signal is found between aa 793 and 798 (The UniProt Consortium, 2019 ). In the lower part of the image, all the missense variants described in this series and by Gowans et al ( 2019 ) are displayed (Gowans et al, 2019 ). Patient 4 splicing variant from our cohort (c.1674+1G>A) falls in intron 15, within exons coding for the coiled coil domain.…”

Systematic analysis and prediction of genes associated with disorders on chromosome X

“…[24][25][26] A splice site variant in KIF4A was identified in a family with four affected males, 27 and this finding was recently strengthened by the identification of additional de novo or inherited variants causing a range of different phenotypic manifestations. 28,29 Focusing on no-disorder genes, 21 (9%) of the NN-predicted genes and 14 (4%) of the non-predicted genes were in SysID (Fig. 3c-d).…”

KIF4A: A potential biomarker for prediction and prognostic of prostate cancer

“…The kinesin superfamily proteins (KIFs), also known as microtubule-dependent motor proteins, can move along microtubules and transport cytoplasmic cargos with energy obtained via ATP hydrolysis. The KIFs are classified into 14 subgroups, according to the different function features [10,11]. One of these proteins, KIF4A, has been reported to be involved in various biological activities, such as cell division, chromosome condensation, spindle organization and cytokinesis [12][13][14].…”