PAK3 mutation in nonsyndromic X-linked mental retardation

Allen, Kristina M.; Gleeson, Joseph G.; Bagrodia, Shubha; Partington, M. W.; MacMillan, John; Cerione, Richard A.; Mulley, John C.; Walsh, Christopher A.

doi:10.1038/1675

Cited by 434 publications

(359 citation statements)

References 36 publications

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“…These mutations have been associated with either loss of PAK3 protein or loss of its kinase activity. 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].…”

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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“…15 All three seem to belong to signal transduction pathways through GTPbinding proteins. 16 FMR2, the first characterised gene responsible for non-specific X-linked mental retardation, however, does not appear to belong to the same pathway.…”

Section: Discussionmentioning

confidence: 99%

Characterisation and expression of a large, 13.7 kb FMR2 isoform.

Gécz

Mulley

1999

Eur J Hum Genet

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FMR2 is the gene associated with FRAXE fragile site non-specific mental retardation (FRAXE MRX). Previously a male patient was identified with developmental delay and speech problems who had a deletion within intron 3 of FMR2. No known FMR2 exonic sequences were missing in this patient. Detailed northern blot analysis revealed existence of a new large isoform of FRM2 in foetal brain. This isoform was characterised and found to be due entirely to an addition of an extra 4.9 kb of the 3' UTR to the previously characterised 8.755 kb FMR2 transcript. This excluded involvement of the large FMR2 isoform in the MRX phenotype of three individuals now known to have the same deletion of intron 3 FMR2 sequences. Expression studies on the new 13.7 kb FMR2 isoform show that it is expressed predominantly in foetal brain and adult pituitary gland, whilst the expression of the shorter previously characterised 8.755 kb isoform is broader, including testis, thymus and placenta. Possible consequences of the alternative processing and expression of FMR2 for the molecular pathology of FRAXE MRX are discussed.

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“…Hence, it is not surprising that mutations in genes encoding regulators and effectors of the Rho GTPases have been found to underlie human neurological diseases. To date, several Rho GTPase-linked genes associated with MR have been identified , including OPHN1 (Bienvenu et al, 1997;Billuart et al, 1998;Govek et al, 2004), PAK3 (Allen et al, 1998;Bienvenu et al, 2000;Boda et al, 2004;Gedeon et al, 2003;Meng et al, 2005) and ARHGEF6 (Kutsche et al, 2000;Node-Langlois et al, 2006). We embarked on the functional characterization of OPHN1.…”

Section: Introduction: Rho Gtpases Synaptic Structure and Functionmentioning

confidence: 99%

Characterization of Oligophrenin‐1, a RhoGAP Lost in Patients Affected with Mental Retardation: Lentiviral Injection in Organotypic Brain Slice Cultures

Kasri

Govek

Aelst

2008

Methods in Enzymology

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Mutations in regulators and effectors of the Rho GTPases underlie various forms of mental retardation (MR). Among them, oligophrenin-1 (OPHN1), which encodes a Rho-GTPase activating protein (Rho-GAP), was one of the first Rho-linked MR gene identified. Upon characterization of OPHN1 in hippocampal brain slices, we obtained evidence for the requirement of OPHN1 in dendritic spine morphogenesis and synaptic function of CA1 pyramidal neurons. Organotypic hippocampal brain slice cultures are commonly used as a model system to investigate the morphology and synaptic function of neurons, mainly because they allow for the long-term examination of neurons in a preparation where the gross cellular architecture of the hippocampus is retained. In addition, the maintenance of the tri-synaptic circuitry in hippocampal slices enables the study of synaptic connections. Today, a multitude of gene transfer methods for postmitotic neurons in brain slices are available to easily manipulate and scrutinize the involvement of signaling molecules, such as Rho GTPases, in specific cellular processes in this system. This chapter covers techniques detailing the preparation and culturing of organotypic hippocampal brain slices, as well as the production and injection of lentivirus into brain slices.

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PAK3 mutation in nonsyndromic X-linked mental retardation

Cited by 434 publications

References 36 publications

Rho-linked genes and neurological disorders

Rho-linked genes and neurological disorders

Characterisation and expression of a large, 13.7 kb FMR2 isoform.

Characterization of Oligophrenin‐1, a RhoGAP Lost in Patients Affected with Mental Retardation: Lentiviral Injection in Organotypic Brain Slice Cultures

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