Genetics of X‐linked Mental Retardation

Lisik, Małgorzata

doi:10.1002/9780470015902.a0020231

Cited by 12 publications

(17 citation statements)

References 45 publications

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“…XLMR are commonly subdivided into two forms of non-syndromic and syndromic on the basis of clinical presentation. The distinction between these two forms of XLMR is becoming less clear since clinical phenotypes are described from several mutations of the genes implicated in both nonsyndromic and syndromic XLMR pedigrees 70 . Dysfunction of PAK might be involved in the pathogenesis of both forms of XLMR, because mutations in the PAK3 gene were found in nonsyndromic X-linked mental retardation (MRX) 20 , 21 and inhibition of PAK activity was found to rescue symptoms of fragile X syndrome (FXS) in FXS mouse models.…”

Section: X-linked Mental Retardationmentioning

confidence: 99%

PAK in Alzheimer disease, Huntington disease and X-linked mental retardation

Yang

Frautschy

et al. 2012

Cellular Logistics

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Developmental cognitive deficits including X-linked mental retardation (XLMR) can be caused by mutations in P21-activated kinase 3 (PAK3) that disrupt actin dynamics in dendritic spines. Neurodegenerative diseases such as Alzheimer disease (AD), where both PAK1 and PAK3 are dysregulated, may share final common pathways with XLMR. Independent of familial mutation, cognitive deficits emerging with aging, notably AD, begin after decades of normal function. This prolonged prodromal period involves the buildup of amyloid-β (Aβ) extracellular plaques and intraneuronal neurofibrillary tangles (NFT). Subsequently region dependent deficits in synapses, dendritic spines and cognition coincide with dysregulation in PAK1 and PAK. Specifically proximal to decline, cytoplasmic levels of actin-regulating Rho GTPase and PAK1 kinase are decreased in moderate to severe AD, while aberrant activation and translocation of PAK1 appears around the onset of cognitive deficits. Downstream to PAK1, LIM kinase inactivates cofilin, contributing to cofilin pathology, while the activation of Rho-dependent kinase ROCK increases Aβ production. Aβ activation of fyn disrupts neuronal PAK1 and ROCK-mediated signaling, resulting in synaptic deficits. Reductions in PAK1 by the anti-amyloid compound curcumin suppress synaptotoxicity. Similarly other neurological disorders, including Huntington disease (HD) show dysregulation of PAKs. PAK1 modulates mutant huntingtin toxicity by enhancing huntingtin aggregation, and inhibition of PAK activity protects HD as well as fragile X syndrome (FXS) symptoms. Since PAK plays critical roles in learning and memory and is disrupted in many cognitive disorders, targeting PAK signaling in AD, HD and XLMR may be a novel common therapeutic target for AD, HD and XLMR.

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Section: X-linked Mental Retardationmentioning

confidence: 99%

PAK in Alzheimer disease, Huntington disease and X-linked mental retardation

Yang

Frautschy

et al. 2012

Cellular Logistics

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“…XLMR is very heterogeneous with more than 60 XLMR genes now identified (Ropers 2006; Lisik and Sieron 2008; Humeau and others 2009). Mutations in some of these genes give rise to clinically distinguishable syndromes, such as fragile X syndrome, Coffin-Lowry syndrome and Rett syndrome, some of which have been discussed above.…”

Section: Synaptic Dysfunction In Mental Disordersmentioning

confidence: 99%

Ras and Rap Signaling in Synaptic Plasticity and Mental Disorders

2010

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The Ras family GTPases (Ras, Rap1, and Rap2) and their downstream mitogen-activated protein kinases (ERK, JNK, and p38MAPK) and PI3K signaling cascades control various physiological processes. In neuronal cells, recent studies have shown that these parallel cascades signal distinct forms of AMPA-sensitive glutamate receptor trafficking during experience-dependent synaptic plasticity and adaptive behavior. Interestingly, both hypo- and hyper-activation of Ras/Rap signaling impair the capacity of synaptic plasticity, underscoring the importance of a “happy-medium” dynamic regulation of the signaling. Moreover, accumulating reports have linked various genetic defects that either up- or down-regulate Ras/Rap signaling with a number of mental disorders associated with learning disability (e.g., Alzheimer’s disease, Angelman syndrome, autism, cardio-facio-cutaneous syndrome, Coffin-Lowry syndrome, Costello syndrome, Cowden and Bannayan-Riley-Ruvalcaba syndromes, fragile X syndrome, neurofibromatosis type 1, Noonan syndrome, schizophrenia, tuberous sclerosis, and X-linked mental retardation), highlighting the necessity of happy-medium dynamic regulation of Ras/Rap signaling in learning behavior. Thus, the recent advances in understanding of neuronal Ras/Rap signaling provide a useful guide for developing novel treatments for mental diseases.

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“…For example, Froyen and colleagues screened a cohort of 108 subjects with ID by X-chromosome array CGH and identified X-chromosome CNVs in 14 subjects (13%) 8. Duplications on the X chromosome correlated with ID more often than expected, suggesting a causal link between increased gene dosage and the disruption of normal cognitive development 3. The most common XLID-associated chromosomal aberrations are duplications of Xq28 comprising the MECP2 gene, which have been reported in more than 100 cognitively impaired individuals with characteristic facial features, hypotonia, seizures, speech delay and recurrent infections 9–12.…”

Section: Introductionmentioning

confidence: 99%

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions

El‐Hattab

Fang

Jin

et al. 2011

Journal of Medical Genetics

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Background X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants. Methods Array CGH analysis was performed using chromosomal microarray with w105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification. Results A novel w0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions. Conclusions The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.

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Genetics of X‐linked Mental Retardation

Cited by 12 publications

References 45 publications

PAK in Alzheimer disease, Huntington disease and X-linked mental retardation

PAK in Alzheimer disease, Huntington disease and X-linked mental retardation

Ras and Rap Signaling in Synaptic Plasticity and Mental Disorders

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions

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