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Review
. 2023 Aug 4:17:1226181.
doi: 10.3389/fnins.2023.1226181. eCollection 2023.

TUBB3 and KIF21A in neurodevelopment and disease

Dharmendra Puri  1   2   3 , Brenda J Barry  1   2   3 , Elizabeth C Engle  1   2   3   4
Affiliations
Review

TUBB3 and KIF21A in neurodevelopment and disease

Dharmendra Puri et al. Front Neurosci. .

Abstract

Neuronal migration and axon growth and guidance require precise control of microtubule dynamics and microtubule-based cargo transport. TUBB3 encodes the neuronal-specific β-tubulin isotype III, TUBB3, a component of neuronal microtubules expressed throughout the life of central and peripheral neurons. Human pathogenic TUBB3 missense variants result in altered TUBB3 function and cause errors either in the growth and guidance of cranial and, to a lesser extent, central axons, or in cortical neuronal migration and organization, and rarely in both. Moreover, human pathogenic missense variants in KIF21A, which encodes an anterograde kinesin motor protein that interacts directly with microtubules, alter KIF21A function and cause errors in cranial axon growth and guidance that can phenocopy TUBB3 variants. Here, we review reported TUBB3 and KIF21A variants, resulting phenotypes, and corresponding functional studies of both wildtype and mutant proteins. We summarize the evidence that, in vitro and in mouse models, loss-of-function and missense variants can alter microtubule dynamics and microtubule-kinesin interactions. Lastly, we highlight additional studies that might contribute to our understanding of the relationship between specific tubulin isotypes and specific kinesin motor proteins in health and disease.

Keywords: CFEOM; KIF21A; TUBB3; microtubule; tublinopathy; tubulin.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Clinical spectrum and cranial nerve imaging of the TUBB3-CFEOM syndromes. (A–I) Photographs of individuals harboring TUBB3-CFEOM variants. R262C can cause bilateral ptosis and severe CFEOM3 with the resting position of both eyes infraducted and abducted (A), moderate CFEOM3 that can be unilateral (B), and mild CFEOM3 (not shown). A similar spectrum is seen with D417N; severe CFEOM3 is shown in (E). A302T (C) and R380C (D) cause moderate to severe CFEOM3. Participants in (A–E) have full facial movements. The axonal neuropathy in the participant with D417N (E) results in atrophy of the intrinsic foot muscles and a high arch (F). E410K (G) and R262H (H) result in severe CFEOM3 and facial weakness, and R262H also results in congenital joint contractures, including ulnar deviation of the hand with joint contractures of the thumbs and fingers (I). (J,K) MRI of the brainstem at the level of the oculomotor (CN III) nerve in control (J) and E410K (K). (L,M) Orbital contents posterior to the globe in control (L) and in an individual with the E410K substitution. Note atrophy of the levator palpebrae superioris (LPS), superior rectus (SR), and medial rectus (MR) muscles in (M). The inferior rectus (IR), lateral rectus (LR), and superior oblique (SO) muscles appear normal. ON denotes optic nerve. (N,O) MRI of the brainstem at the level of the superior internal auditory meati to visualize the facial (CN VII, blue arrows) and vestibulocochlear (CN VIII, red arrows) nerves. In a control individual (N), CN VII courses parallel and ventral to CN VIII on each side. The anterior inferior cerebellar artery flow void is seen between the cranial nerves on the right (yellow arrowhead). In an individual with R262H substitution, CN VII appears hypoplastic and is faintly visualized coursing ventral and parallel to the cranial nerves VIII. (A–L) Reproduced with permission from Tischfield et al. (2010); (N,O) reproduced with permission from Whitman et al. (2021).
Figure 2
Figure 2
Spectrum of TUBB3-CFEOM brain malformations correlates with specific TUBB3 variants. (A–G) Midline sagittal MRI showing the spectrum of corpus callosum (CC) dysgenesis; corresponding amino acid substitutions are noted to the left. R62Q (A) and most R262C (B) subjects have normal corpus callosum development, whereas D417N subjects have hypoplasia of the posterior body (C, arrow). Subjects with A302T, E410K, and R262H have diffuse corpus callosum hypoplasia (D–F). (G) R380C subjects can have corpus callosal agenesis and brainstem (arrow) and mild vermian hypoplasia (asterisk). (H–N) Axial MRI from the same subjects’ scans showing the spectrum of anterior commissure (AC) dysgenesis and overall loss of white matter compared to the normal R62Q scan (H, arrow indicates AC). (I–L) Subjects have hypoplastic AC. R262H (M) and R380C (N) subjects have anterior commissure agenesis and dysmorphic basal ganglia. The anterior limb of the left internal capsule is hypoplastic in R262H (M, arrow), whereas there is lack of clear separation between the caudate and putamen and bilateral hypoplasia of the anterior limbs of the internal capsule with R380C (N, arrows). (O–V) Anterior (O–R) and posterior (S–V) coronal sections showing the spectrum of basal ganglia dysmorphisms. Compared to a TUBB3+/+ scan (O,S), the R262C scan reveals asymmetric basal ganglia with enlargement of the left caudate head and putamen (P, arrow) and hypoplasia of the left caudate body (T, arrows). The R262H scan reveals dysgenesis of the left and right anterior limbs of the internal capsule (Q, arrows), apparent fusion of an enlarged left caudate head with the putamen (Q), hypoplasia of the left caudate body and tail (U), and asymmetrical dilatation of the lateral ventricles. The R380C scan reveals hypoplasia of the anterior limb of the internal capsule (R, arrow), fusion of the left caudate head and underlying putamen with bilateral hypoplasia of the caudate body and tail (V, arrows), and Probst bundles of callosal axons that line the bodies of the lateral ventricles (V, arrowheads). (W,X) Coronal images of olfactory sucli (OS, black arrows) and bulbs (OB, white arrows) in a control (W) compared to a subject with the E410K substitution (X). The E410K subject has olfactory sulcus agenesis and bulb dysgenesis (X, white arrows). (A–V) Reproduced with permission from Tischfield et al. (2010). (W,X) Reproduced with permission from Chew et al. (2013).
Figure 3
Figure 3
TUBB3-MCD brain malformations in individual harboring a TUBB3 T178M substitution. 17-month-old born at term presented with microcephaly, global developmental delay, axial hypotonia, appendicular hypertonia, and infantile spasms and underwent MR imaging. (A) Midline sagittal MR image: agenesis of the corpus callosum and anterior commissure, dysmorphic dilated ventricles, uplifted hypoplastic cerebellar vermis with enlarged CSF spaces, effaced aqueduct, malformed brainstem with flattened pons (asterisk). (B) Posterior coronal MR image: enlarged ventricles (V), bilateral hypoplasia of the caudate body and tail (white arrowhead), abnormal under-rotated left hippocampus (white arrow), abnormally oriented cerebellar folia, and thickened malformed cortex in the left Sylvian fissure (red boxed region). (C) Caudal axial MR image: hypoplastic malformed cerebellar vermis (black arrow) and hemispheres, flatted left pyramidal track (black arrowhead) and enlarged CFS spaces. (D) Rostral axial MR image: malformation of the basal ganglia with fusion of the caudate and putamen with no visible anterior limb of the internal capsule (black arrow), rounded globular-appearing thalami (T), ventricular enlargement, and thickened malformed cortex around the left Sylvian fissure (red boxed region).
Figure 4
Figure 4
Human TUBB3 amino acid substitutions. (A–F) Three-dimensional schematics of TUBB3 structure with locations of reported TUBB3 human substitutions highlighted generated using PyMol (https://www.rcsb.org/structure/1JFF) and rotated to reveal: ‘external views’ (row 1; A,C,E displayed as heterodimers with α-tubulin) and ‘side views’ (row 2: B,D,F, displayed as β-tubulin monomers) highlighting helices H11 (green) and H12 (yellow) on the outside of the cylindrical hollow microtubule. TUBB3-CFEOM substitutions are highlighted in magenta and TUBB3-CFEOM/MCD in purple (A,B). These substitutions are most often found in the C-terminal domain on or adjacent to helix H12 (yellow) on residues where motor protein interact. The exceptions are: R380 on helix H11 (green) and A302 that may interact with H11; R62 located in a loop mediating lateral interactions; and S78 together with TUBB3-CFEOM/MCD substitutions at G71 and G98 which cluster together and away from other variants near the E site of the GTP binding pocket. TUBB3-MCD substitutions are highlighted in orange (C,D). These substitutions are located primarily in regions that regulate GTP binding, heterodimer stability, and longitudinal and lateral interactions and away from variants in (A,B). Exceptions are A302 which is altered to a different residue in TUBB3-CFEOM and is located within a loop that could be important for both heterodimer stability and MAP/motor protein interactions. Similarly, M388 could regulate MAP/motor protein interactions, and is in proximity to residues at the plus-end of β-tubulin that mediate inter heterodimer contacts. TUBB3-nonCFEOM/nonMCD substitutions are highlighted in turquois (E,F). These substitutions are also removed from H11/H12 helices and are located in regions that regulate heterodimer stability and longitudinal and lateral interactions. Refer to Tischfield et al. (2011) for 3D domain schematics. (G) Two-dimensional schematic of TUBB3 N-terminal, intermediate, and C-terminal domains with human amino acid substitutions indicated. TUBB3-CFEOM (magenta), TUBB3-CFEOM/MCD (purple), and TUBB3-nonCFEOM/nonMCD (cyan) amino acid substitutions are shown above, while TUBB3-MCD amino acid substitutions (orange) are shown below the TUBB3 protein schematic.
Figure 5
Figure 5
Human KIF21A amino acid substitutions. (A) Three-dimensional schematic of the D. melanogaster kinesin-1 motor domain dimer (https://www.rcsb.org/structure/2Y5W) with the four human variants that alter residues in the motor domain mapped to the monomer on the right. C28 and M345 that cause isolated CFEOM are denoted in magenta and D352 and F355 that cause more syndromic CFEOM are denoted in black. The variants cluster on the lateral region of the motor domain removed from the ATP and microtubule binding sites. Data supports this as the site of the motor-third coiled-coil stalk domain interaction for KIF21A autoinhibition. (B) Two-dimensional schematic of KIF21A motor (blue), stalk (gray) and WD40 (green) domains. The coiled-coil regions of the stalk are denoted in yellow. Substitutions that cause isolated CFEOM are denoted in magenta above the KIF21A schematic. In addition to the two motor substitutions, note the clustering of KIF21A-CFEOM substitutions in the third coiled-coil region of the stalk. This region has been demonstrated to interact with the lateral aspect of the motor domain. The three substitutions that cause more syndromic CFEOM are noted in black below the KIF21A schematic. In addition to the two in the distal motor domain, L685P maps to the second coiled-coil and results in a syndromic phenotype similar to the E410K TUBB3 syndrome.
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