'Kinesinopathies': emerging role of the kinesin family member genes in birth defects

Abstract

Motor kinesins are a family of evolutionary conserved proteins involved in intracellular trafficking of various cargoes, first described in the context of axonal transport. They were discovered to have a key importance in cell-cycle dynamics and progression, including chromosomal condensation and alignment, spindle formation and cytokinesis, as well as ciliogenesis and cilia function. Recent evidence suggests that impairment of kinesins is associated with a variety of human diseases consistent with their functions and evolutionary conservation. Through the advent of gene identification using genome-wide sequencing approaches, their role in monogenic disorders now emerges, particularly for birth defects, in isolated as well as multiple congenital anomalies. We can observe recurrent phenotypical themes such as microcephaly, certain brain anomalies, and anomalies of the kidney and urinary tract, as well as syndromic phenotypes reminiscent of ciliopathies. Together with the molecular and functional data, we suggest understanding these 'kinesinopathies' as a recognisable entity with potential value for research approaches and clinical care.

Keywords: clinical genetics.

Figure 1

Phylogenetic tree of mammalian kinesin superfamily genes identified in the human (and mouse) genome and classified in 16 subfamilies (from kinesin 1 to 14B) (adapted from Hirokawa et al 3).

Figure 2

Assignment and clustering of KIF genes to various functions and relation to birth defect or monogenic phenotype groups. Detailed phenotypes are shown in tables 1 and 3. Cancer and multifactorial conditions are not included. CNS, central nervous system.

Figure 3

Structure of KIF14 and summary of all published KIF14 variants affecting function. The N-terminal region (aa 1–356) is important for its interactions with PRC1 and the protein’s localisation at the central spindle and midbody; the kinesin motor domain (aa 358–701) is responsible for the microtubule-dependent ATPase activity; the FHA domain (aa 825–891); stalk and tail region (aa 891–1648) are necessary for the interaction with the protein CRIK (aa 901–1189, red diagonal lines). There are four additional coiled-coil domains (light blue-coloured areas). FHA, forkhead associated. aa, amino acid.

Figure 4

IPA of the 13 kinesins known to be involved in birth defects with respect to their position in the cell. Proteins displayed on the right side of the figure, below the tag ‘other’, are those for which no subcellular location is known. Birth defect-related kinesins and their connection with each other are highlighted in green. Light blue-coloured downstream proteins are those which are known to cause birth defects when altered. Yellow-coloured proteins are those involved in neurological disorders overlapping with the clinical features of kinesinopathies. The legend of the biological function associated with every molecule is displayed on the right. Path Designer by IPA was used for the figure design. IPA, Ingenuity Pathway Analysis.