TUBB3 and KIF21A in neurodevelopment and disease

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.

Profiling of immune infiltration landscape of ruptured intracranial aneurysm

“…[37] In addition, abnormal expression of KIF21A, an anterograde kinesin-motor protein that directly interacts with microtubules, plays an important role in various nervous system related diseases in humans. [38] IA formation is characterized by destruction of and cystic formation in arterial wall. Animal studies have suggested that pathological changes of vascular smooth muscle cells in tunica media is an important part of formation of aneurysms, which were also confirmed in our study.…”

“…[ 37 ] In addition, abnormal expression of KIF21A, an anterograde kinesin-motor protein that directly interacts with microtubules, plays an important role in various nervous system related diseases in humans. [ 38 ]…”

Identification of two novel and one rare mutation in DYRK1A and prenatal diagnoses in three Chinese families with intellectual Disability-7

“…The c.-115C>G and c.*286A>T variants of TUBB3 could give rise to the dysfunction of neuronal-specific β-tubulin isotype III, which may lead to compound cortical dysplasia with other brain developmental abnormalities type 1 associated with the syndrome of MRD7, however, the location of TUBB3 variant is in the non-coding region and comprehensively estimated as LP. The c.194C>T and c.874A>G variants of NALCN were inherited from proband’s father and were estimated as VUS, her father did not show the symptoms of the same variants of NALCN and the certain variants’ pathogenic proof were not retrieved in the database presented as before ( Radwitz et al, 2022 ; Puri et al, 2023 ). The 16p12.2del variants were inherited from the proband’s mother, which was estimated as pathogenic for her mother’s corresponding symptoms.…”