Clinical and Molecular Aspects of the Neurodevelopmental Disorder Associated with PAK3 Perturbation

Pascolini, Giulia; Gaudioso, Federica; Passarelli, Chiara; Novelli, Antonio; Giosaffatte, Niccolò Di; Majore, Silvia; Grammatico, Paola

doi:10.1007/s12031-021-01868-w

Cited by 3 publications

(6 citation statements)

References 21 publications

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“…Brain MRI abnormalities have also been reported in two affected fetuses, including agenesis of the corpus callosum agenesis, abnormal conformation of the brainstem and pyramidal tract, hydrocephalus, and subependymal cysts [ 154 , 155 ]. Symptomatic females are rare and present with intellectual disability and behavioural disturbances, occasionally associated with brain abnormalities and abnormal eye movements [ 156 ].…”

Section: Implications Of Rac Proteins Effectors and Regulators In Nddsmentioning

confidence: 99%

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

Scala

Nishikawa

Nagata

et al. 2021

Cells

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Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1–3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies.

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Section: Implications Of Rac Proteins Effectors and Regulators In Nddsmentioning

confidence: 99%

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

Scala

Nishikawa

Nagata

et al. 2021

Cells

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“…The first variation responsible for such a case is the p.(Lys389Thr), which was also the second described substitution affecting the Lys389 residue. The patient bearing this mutation displayed ID, secondary microcephaly and ADHD (Pascolini et al, 2021). The published p.(Pro229Ser) variation indexed in PAK3cb, which corresponds to a p.(Pro193Ser) variation in the PAK3a isoform (Figure 3B), is associated with ID, microcephaly and combined immunodeficiency syndrome in the proband girl (Almutairi et al, 2021).…”

Section: Introductionmentioning

confidence: 93%

“…There are also some non-neurological symptoms associated with PAK variants. Interestingly, skin anomalies, such as café-au-lait spots, were described for the majority of patients bearing PAK1 mutations and associated with some PAK3 variations (Magini et al, 2014;Hertecant et al, 2017;Harms et al, 2018;Pascolini et al, 2021). These anomalies may be due to defects in the activation of the Ras-MAP kinase pathway, leading to RASopathy (Magini et al, 2014).…”

Section: Pak2 Variants Are Associated With Asdmentioning

confidence: 99%

“…Whether this variant is responsible for haploinsufficiency is still unknown. For PAK3, most variants are inherited and only two of them, p.(Lys389Thr) and p.(Ser527Gly) occurred de novo (Horvath et al, 2018;Pascolini et al, 2021).…”

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

confidence: 99%

“…Although skewed X-inactivation has been observed in several women, this could not be correlated with clinical characteristics. Unfortunately, there are no further data on more recently identified female probands (Almutairi et al, 2021;Pascolini et al, 2021). Despite the difference between men and women in PAK-associated disease transmission, no evidence suggests that differences in PAK functions exist between the two sexes.…”

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

confidence: 99%

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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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Transcriptome Sequencing Analysis Reveals Dynamic Changes in Major Biological Functions during the Early Development of Clearhead Icefish, Protosalanx chinensis

Tang

Jiang

Wang

et al. 2022

Fishes

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Early development, when many important developmental events occur, is a critical period for fish. However, research on the early development of clearhead icefish is very limited, especially in molecular research. In this study, we aimed to explore the dynamic changes in the biological functions of five key periods in clearhead icefish early development, namely the YL (embryonic), PM (first day after hatching), KK (fourth day after hatching), LC (seventh day after hatching), and SL (tenth day after hatching) stages, through transcriptome sequencing and different analysis strategies. A trend expression analysis and an enrichment analysis revealed that the expression ofgenes encoding G protein-coupled receptors and their ligands, i.e., prss1_2_3, pomc, npy, npb, sst, rln3, crh, gh, and prl that are associated with digestion and feeding regulation gradually increased during early development. In addition, a weighted gene co-expression network analysis (WGCNA) showed that eleven modules were significantly associated with early development, among which nine modules were significantly positively correlated. Through the enrichment analysis and hub gene identification results of these nine modules, it was found that the pathways related to eye, bone, and heart development were significantly enriched in the YL stage, and the ccnd2, seh1l, kdm6a, arf4, and ankrd28 genes that are associated with cell proliferation and differentiation played important roles in these developmental processes; the pak3, dlx3, dgat2, and tas1r1 genes that are associated with jaw and tooth development, TG (triacylglycerol) synthesis, and umami amino acid receptors were identified as hub genes for the PM stage; the pathways associated with aerobic metabolism and unsaturated fatty acid synthesis were significantly enriched in the KK stage, with the foxk, slc13a2_3_5, ndufa5, and lsc2 genes playing important roles; the pathways related to visual perception were significantly enriched in the LC stage; and the bile acid biosynthetic and serine-type peptidase activity pathways were significantly enriched in the SL stage. These results provide a more detailed understanding of the processes of early development of clearhead icefish.

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Clinical and Molecular Aspects of the Neurodevelopmental Disorder Associated with PAK3 Perturbation

Cited by 3 publications

References 21 publications

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

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

Transcriptome Sequencing Analysis Reveals Dynamic Changes in Major Biological Functions during the Early Development of Clearhead Icefish, Protosalanx chinensis

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