Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation

Bienvenu, Thierry; Portes, Vincent Des; McDonell, Nathalie; Carrié, Alain; Zemni, Ramzi; Couvert, Philippe; Ropers, Hans Hilger; Moraine, Claude; Bokhoven, Hans van; Fryns, J. P.; Allen, Keri; Walsh, Christopher A.; Boué, J; Kahn, Axel; Chelly, Jamel; Beldjord, Chérif

doi:10.1002/1096-8628(20000814)93:4<294::aid-ajmg8>3.0.co;2-f

Cited by 130 publications

(94 citation statements)

References 17 publications

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“…The first PAK3 mutation, R419X, found in family MRX30, introduces a premature stop codon that abolishes the kinase activity of the truncated product [1]. The second PAK3 mutation, an R67C missense mutation in family MRX47, likely affects GTPase binding and activation of PAK3 [7]. The consequence of the third mutation (A365E), also a missense mutation, on PAK3 function is not yet defined, although it occurs in a highly conserved region of the protein that may affect catalytic kinase domain function [29].…”

Section: Pak3mentioning

confidence: 99%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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Section: Pak3mentioning

confidence: 99%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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“…One of the main downstream effectors of Rac is p21-activated kinase (PAK), a family of serine-threonine kinases that is composed of at least three members, PAK1, PAK2, and PAK3 (16). Notably, loss-offunction mutations in the PAK3 gene are associated with nonsyndromic X-linked mental retardation (17,18).Strikingly, in transgenic (TG) mice in which PAK activity is inhibited by its dominant negative (dn) form (dnPAK), cortical spine morphology exhibits features that are opposite to those seen in FXS patients and FMR1 KO mice (19). Specifically, cortical neurons in the dnPAK TG mice have fewer dendritic spines and a lower proportion of longer and thinner spines.…”

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confidence: 99%

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Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice

Hayashi

Rao

Seo

et al. 2007

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

248

235

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Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical longterm potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.cortical long-term potentiation ͉ spine morphology ͉ trace fear conditioning ͉ autism F ragile X syndrome (FXS), the most commonly inherited form of mental retardation and the most common cause of autism, is caused by the loss of the fragile X mental retardation protein (FMRP) encoded by the fragile X mental retardation 1 (FMR1) gene (1). Although moderate to severe mental retardation and a developmental delay are the key features of FXS, patients also display problems related to anxiety, attention deficit, hyperactivity, stereotypy, seizure, and social behavior. FMR1 knockout (KO) mice (2), which exhibit phenotypes similar to those seen in FXS in humans, have served as a useful model system for investigating how the absence of FMRP leads to the various molecular, cellular, and behavioral abnormalities observed in the disorder. Although these studies have led to valuable insights into the etiology of FXS, there has not been effective treatment of this debilitating disorder.Several key observations are strongly suggestive of a primary role of defects in dendritic spines and synaptic plasticity in the symptoms associated with FXS (3). Increased numbers of dendritic spines and an abundance of long and immature spines have been reported in FXS individuals and FMR1 KO mice (4-7). FMRP and its mRNA are found in dendrites and spines, the sites of transmission and plastic...

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“…The derangement of Rho GTPase signaling, which is consistently found in MR, is believed to underlie this feature (18)(19)(20)(21). In particular, a deficit in activated Rho GTPases or their effector proteins has been demonstrated in some forms of MR (18,(21)(22)(23)). This finding is compatible with the activating effects of Rac-GTP and Cdc42-GTP on actin cytoskeleton (8,24).…”

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confidence: 99%

Enhancement of learning and memory after activation of cerebral Rho GTPases

Diana

Valentini

Travaglione

et al. 2007

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

119

115

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The mechanism whereby the morphology and connectivity of the dendritic tree is regulated depends on an actin dynamics that, in turn, is controlled by Rho GTPases, a family of small GTP-binding proteins encompassing Rho, Rac, and Cdc42 subfamilies. Cytotoxic necrotizing factor 1 (CNF1), a protein toxin from Escherichia coli, constitutively activates Rho GTPases, thus leading to remodeling of the actin cytoskeleton in intact cells. Here, we show that the modulation of cerebral RhoA and Rac1 activity induced by CNF1 in mice leads to (i) rearrangement of cerebral actin cytoskeleton, (ii) enhanced neurotransmission and synaptic plasticity, and (iii) improved learning and memory in various behavioral tasks. The effects persist for weeks and are not observed in mice treated with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine to cysteine at position 866. The results suggest that learning ability can be improved through pharmacological manipulation of neural connectivity.cytotoxic necrotizing factor 1 ͉ brain ͉ bacterial toxins ͉ dendritic spines ͉ drug therapy

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Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation

Cited by 130 publications

References 17 publications

Rho-linked genes and neurological disorders

Rho-linked genes and neurological disorders

Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice

Enhancement of learning and memory after activation of cerebral Rho GTPases

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