A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features

Rejeb, Imen; Saillour, Yoann; Castelnau, L.; Julien, Cédric; Bienvenu, Thierry; Taga, Patricia; Chaâbouni, Habiba; Chelly, Jamel; Jemaa, Lamia Ben; Bahi‐Buisson, Nadia

doi:10.1038/ejhg.2008.103

Cited by 35 publications

(24 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Investigating these molecular mechanisms may have significance in addition to that for psychosis in AD and schizophrenia, considering human genetic research has identified mutations in PAK3 that lead to variants of X-linked intellectual disability associated with psychotic behaviors (Gedeon et al, 2003; Rejeb et al, 2008). Description of the behavioral and associated morphological changes may provide insight into the role of the kalirin-PAK pathway in generating psychosis-associated behaviors in neuropsychiatric disease.…”

Section: Discussionmentioning

confidence: 99%

Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice

Krivinko

Erickson

Abrahamson

et al. 2017

Neurobiology of Aging

View full text Add to dashboard Cite

Psychosis in Alzheimer disease (AD+P) represents a distinct clinical and neurobiological AD phenotype, and is associated with more rapid cognitive decline, higher rates of abnormal behaviors, and increased caregiver burden compared to AD without psychosis. On a molecular level, AD+P is associated with greater reductions in the protein kalirin, a guanine exchange factor which has also been linked to the psychotic disease, schizophrenia. In this study, we sought to determine the molecular and behavioral consequences of kalirin reduction in APPswe/PSEN1dE9 mice. We evaluated mice with and without kalirin reduction during tasks measuring psychosis-associated behaviors and spatial memory. We found that kalirin reduction in APPswe/PSEN1dE9 mice significantly attenuated psychosis-associated behavior at 12 months of age without changing spatial memory performance. The 12 month old APPswe/PSEN1dE9 mice with reduced kalirin levels also had increased levels of the active, phosphorylated form of p21 protein (Cdc42/Rac)-activated kinases (PAKs), which function in signaling pathways for maintenance of dendritic spine density, morphology, and function.

show abstract

Section: Discussionmentioning

confidence: 99%

Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice

Krivinko

Erickson

Abrahamson

et al. 2017

Neurobiology of Aging

View full text Add to dashboard Cite

show abstract

“…Indeed, PAK3 and ARHGEF6 loss-of-function mutations are sufficient to cause a form of X-linked intellectual disability (31, 32, 51), and are thought to work together in a complex (52). Additionally, in one large family pedigree, psychiatric symptoms occur in individuals with a PAK3 coding mutation (A365E) located in the kinase domain that abolishes PAK3 kinase activity (35, 51, 53). PAK1–3 mRNA levels have also recently shown to be differentially expressed in post-mortem studies of schizophrenic brains (54).…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1–PAK3 signaling in neuroplasticity

et al. 2016

View full text Add to dashboard Cite

While the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent exome sequencing studies of SCZ have uncovered numerous single nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes. Here we demonstrate loss-of-function effects of multiple rare coding SNVs found in SCZ subjects in the GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) gene using functional cell-based assays involving co-expression of GIT1 and PAK3 (p21 protein (Cdc42/Rac)-activated kinase 3). Most notably, a GIT1-R283W variant reported in four independent SCZ cases was defective in activating PAK3 as well as MAPK (Mitogen-activated protein kinase). Similar functional deficits were found for a de novo SCZ variant GIT1-S601N. Additional assays revealed deficits in GIT1-R283W’s capacity to stimulate PAK phosphorylation in cultured hippocampal neurons. Also, GIT1-R283W showed deficits in the induction of GAD1 (Glutamate decarboxylase 1) protein expression. Extending these functional assays to ten additional rare GIT1 variants revealed the existence of an allelic series with the majority of the SCZ case variants exhibiting loss-of-function towards MAPK activation in a manner correlated with loss of PAK3 activation. Taken together, we propose that rare variants in GIT1, along with other genetic and environmental factors, cause dysregulation of PAK3 leading to synaptic deficits in SCZ.

show abstract

“…Despite the differences, these studies together suggest that mutations of genes involved in the RAC-PAK signaling pathway might cause schizophrenia or other related mental illnesses. Indeed, abnormal expressions or mutations of genes in this RAC-PAK pathway have been reported in human genomic studies of patients with psychotic symptoms (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and wellcharacterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.genetic model | rolipram S chizophrenia is a neurodevelopmental disorder with genetic predispositions (1, 2). Although the etiology and neuropathology of schizophrenia are still elusive, functional and neuroanatomical studies from patients have documented various abnormalities in the diseased brain. In particular, defects in neuronal connectivity during development have been proposed as an important precipitating factor for schizophrenia, which is thought to be unmasked by other developmental events or environmental stressors later in life (3). It is therefore likely that some of the major schizophrenia susceptibility genes are important for regulating axonal connections during development.In recent years, the effort to search for genes susceptible to schizophrenia has led to the identification of the Disrupted-inSchizophrenia 1 (DISC1) gene, whose mutation is highly associated with schizophrenia and other major human mental diseases (4). DISC1 has roles in neuron proliferation, neuron migration, axon outgrowth, and synapse formation/maturation (5-8). In our previous studies, we identified an unexpected role of DISC1 in regulating the guidance of developing axons in the adult-born hippocampal dentate granule cells (5, 9). These effects expand the known functions of DISC1 but sheds little light on how DISC1 effects axon guidance.To systemically study the role of DISC1 in axon guidance and to identify the signaling pathways that might be involved, we set out to establish a heterologous genetic system in the nematode Ca...

show abstract

A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features

Cited by 35 publications

References 18 publications

Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice

Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1–PAK3 signaling in neuroplasticity

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Contact Info

Product

Resources

About