Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis

Qian, Xuyu; DeGennaro, Ellen M; Talukdar, Maya; Akula, Shyam; Lai, Abbe; Shao, Diane D.; Gonzalez, Dilenny M.; Marciano, Jack H.; Smith, Richard; Hylton, Norma K.; Yang, Edward; Bazán, J. Fernando; Barrett, Lee C.; Yeh, Rebecca C.; Hill, Robert S.; Beck, Samantha G.; Otani, Aoi; Jolly, Angad; Mitani, Tadahiro; Posey, Jennifer E.; Pehlivan, Davut; Calame, Daniel G.; Aydın, Hatip; Yeşilbaş, Osman; Parks, Kendall C.; Argilli, Emanuela; England, Eleina; Im, Kiho; Taranath, Ajay; Scott, Hamish S.; Barnett, Christopher; Arts, Peer; Sherr, Elliott H.; Lupski, James R.; Qian, Xuyu

doi:10.1016/j.devcel.2022.09.011

Cited by 10 publications

(7 citation statements)

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“…Sequencing of our cohort identified polymicrogyria cases associated with de novo variants in SCN2A, as well as rare inherited variants in TMEM161B, KIF26A , and MAN2C1 . Details of these associations have been recently reported ( TMEM161B , MAN2C1 , KIF26A , and SCN2A ).…”

Section: Resultsmentioning

confidence: 88%

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

et al. 2023

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ImportancePolymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.ObjectiveTo survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations.Design, Setting, and ParticipantsThis genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control.Main Outcomes and MeasuresThe number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed.ResultsIn 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families.Conclusions and RelevanceThis study’s findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.

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Section: Resultsmentioning

confidence: 88%

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

et al. 2023

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“…Although it is dispensable for the new-born pyramidal neurons to reach the intermediate zone and convert to a bipolar shape, Kif21b paces the glia-guided locomotion by controlling nucleokinesis, dynamic branching and pausing of migrating neurons. To date, several members of the kinesin superfamily have been shown to play critical functions during radial migration (Akkaya et al, 2021; Broix et al, 2016; Carabalona et al, 2016; Falnikar et al, 2011; Falnikar et al, 2013; Gilet et al, 2020; Li et al, 2022; Muralidharan et al, 2022; Qian et al, 2022; Sapir et al, 2013; Yu et al, 2020). Yet, unlike Kif21b, many of them regulate the initial multipolar-to-bipolar transition (Broix et al, 2016; Falnikar et al, 2013; Gilet et al, 2020; Qian et al, 2022; Sapir et al, 2013; Yu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…To date, several members of the kinesin superfamily have been shown to play critical functions during radial migration (Akkaya et al, 2021; Broix et al, 2016; Carabalona et al, 2016; Falnikar et al, 2011; Falnikar et al, 2013; Gilet et al, 2020; Li et al, 2022; Muralidharan et al, 2022; Qian et al, 2022; Sapir et al, 2013; Yu et al, 2020). Yet, unlike Kif21b, many of them regulate the initial multipolar-to-bipolar transition (Broix et al, 2016; Falnikar et al, 2013; Gilet et al, 2020; Qian et al, 2022; Sapir et al, 2013; Yu et al, 2020). Noteworthy, dynamic analysis of each stage of migration (multipolar-to-bipolar transition or bipolar locomotion) has not been performed systematically, preventing the exact delineation of the functions of those kinesins during radial migration.…”

Section: Discussionmentioning

confidence: 99%

The kinesin Kif21b regulates radial migration of cortical projection neurons through a non-canonical function on actin cytoskeleton

Alvarez

Asselin

Tilly

et al. 2023

Preprint

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Completion of neuronal migration is critical for brain development. Kif21b is a plus-end directed kinesin motor protein that promotes intracellular transport and controls microtubule dynamics in neurons. Here we report a physiological function of Kif21b during radial migration of projection neurons in the mouse developing cortex. In vivo analysis in mouse and live imaging on cultured slices demonstrate that Kif21b regulates the radial glia-guided locomotion of new-born neurons independently of its motility on microtubules. Unexpectedly we show that Kif21b directly binds and regulates the actin cytoskeleton both in vitro and in vivo in migratory neurons. We establish that Kif21b-mediated regulation of actin cytoskeleton dynamics influences branching and nucleokinesis during neuronal locomotion. Altogether, our results reveal atypical roles of Kif21b on the actin cytoskeleton during migration of cortical projection neurons.

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“…The second proline-rich sequence is not completely conserved between the different PAK proteins and GRB2 interaction was only demonstrated for PAK1 (Puto et al, 2003). This pathway is probably impacted by mutation of the non-conventional kinesin KIF26A that inhibits GRB2, as observed in patients with severe brain malformations (Qian et al, 2022).…”

Section: Variations In Functional Domainsmentioning

confidence: 97%

The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

Dobrigna

Poëa-Guyon²,

Rousseau³

et al. 2023

Front. Neurosci.

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Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding of their etiology, there are still major obstacles in the way of developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical and genetic heterogeneity, rarity of recurrent pathogenic variants, and comorbidity with other psychiatric traits. Moreover, a large intragenic mutational landscape is at play in some NDDs, leading to a broad range of clinical symptoms. Such diversity of symptoms is due to the different effects DNA variations have on protein functions and their impacts on downstream biological processes. The type of functional alterations, such as loss or gain of function, and interference with signaling pathways, has yet to be correlated with clinical symptoms for most genes. This review aims at discussing our current understanding of how the molecular changes of group I p21-activated kinases (PAK1, 2 and 3), which are essential actors of brain development and function; contribute to a broad clinical spectrum of NDDs. Identifying differences in PAK structure, regulation and spatio-temporal expression may help understanding the specific functions of each group I PAK. Deciphering how each variation type affects these parameters will help uncover the mechanisms underlying mutation pathogenicity. This is a prerequisite for the development of personalized therapeutic approaches.

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Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis

Cited by 10 publications

References 68 publications

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria

The kinesin Kif21b regulates radial migration of cortical projection neurons through a non-canonical function on actin cytoskeleton

The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

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