Short case report: Xq23 deletion involving PAK3 as a novel cause of developmental delay in a 6-year-old boy

Cartwright, Ashley; Smith, Kath; Balasubramanian, Meena

doi:10.1097/mcd.0000000000000154

Cited by 5 publications

(2 citation statements)

References 11 publications

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“…PAK also phosphorylates myosin II by inhibiting MLC kinase (MLCK; Sanders et al, 1999 ). Mutations in PAK1 are associated with developmental delay, macrocephaly, and seizures ( Cartwright et al, 2017 ; Hertecant et al, 2017 ; Harms et al, 2018 ; Horn et al, 2019 ). In cINs, Dlx1/2 represses PAK3 to promote cell migration, while it is activated once cINs reach their final position when it regulates dendritic growth and postsynaptic differentiation ( Cobos et al, 2007 ; Dai et al, 2014 ).…”

Section: Cell-intrinsic Regulation Of Cin Migration Dynamicsmentioning

confidence: 99%

Interneuron odyssey: molecular mechanisms of tangential migration

Toudji,

Toumi,

Chamberland

et al. 2023

Front. Neural Circuits

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Cortical GABAergic interneurons are critical components of neural networks. They provide local and long-range inhibition and help coordinate network activities involved in various brain functions, including signal processing, learning, memory and adaptative responses. Disruption of cortical GABAergic interneuron migration thus induces profound deficits in neural network organization and function, and results in a variety of neurodevelopmental and neuropsychiatric disorders including epilepsy, intellectual disability, autism spectrum disorders and schizophrenia. It is thus of paramount importance to elucidate the specific mechanisms that govern the migration of interneurons to clarify some of the underlying disease mechanisms. GABAergic interneurons destined to populate the cortex arise from multipotent ventral progenitor cells located in the ganglionic eminences and pre-optic area. Post-mitotic interneurons exit their place of origin in the ventral forebrain and migrate dorsally using defined migratory streams to reach the cortical plate, which they enter through radial migration before dispersing to settle in their final laminar allocation. While migrating, cortical interneurons constantly change their morphology through the dynamic remodeling of actomyosin and microtubule cytoskeleton as they detect and integrate extracellular guidance cues generated by neuronal and non-neuronal sources distributed along their migratory routes. These processes ensure proper distribution of GABAergic interneurons across cortical areas and lamina, supporting the development of adequate network connectivity and brain function. This short review summarizes current knowledge on the cellular and molecular mechanisms controlling cortical GABAergic interneuron migration, with a focus on tangential migration, and addresses potential avenues for cell-based interneuron progenitor transplants in the treatment of neurodevelopmental disorders and epilepsy.

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Section: Cell-intrinsic Regulation Of Cin Migration Dynamicsmentioning

confidence: 99%

Interneuron odyssey: molecular mechanisms of tangential migration

Toudji,

Toumi,

Chamberland

et al. 2023

Front. Neural Circuits

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“…The landscape of genetic abnormalities of the three PAK genes is also particular insofar as current published data are mainly made up of missense mutations. For the three genes combined, there are twenty-three missense mutations, two nonsense mutations and one splice site mutation inducing a frameshift, as well as one multi-exonic deletion (Cartwright et al, 2017). There are only few recurrences.…”

Section: Pak Genetic Context Governs the Expression Of Patient Condit...mentioning

confidence: 99%

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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