Talk:Fragile X Syndrome - Revision history

Z8600021 at 03:54, 5 April 2018

2018-04-05T03:54:46Z

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	==2018==		==2018==

			===Reevaluation of FMR1 Hypermethylation Timing in Fragile X Syndrome===

			Front Mol Neurosci. 2018 Feb 6;11:31. doi: 10.3389/fnmol.2018.00031. eCollection 2018.

			Mor-Shaked H1,2, Eiges R1,2.

			Abstract

			Fragile X syndrome (FXS) is one of the most common heritable forms of cognitive impairment. It results from a fragile X mental retardation protein (FMRP) protein deficiency caused by a CGG repeat expansion in the 5'-UTR of the X-linked FMR1 gene. Whereas in most individuals the number of CGGs is steady and ranges between 5 and 44 units, in patients it becomes extensively unstable and expands to a length exceeding 200 repeats (full mutation). Interestingly, this disease is exclusively transmitted by mothers who carry a premutation allele (55-200 CGG repeats). When the CGGs reach the FM range, they trigger the spread of abnormal DNA methylation, which coincides with a switch from active to repressive histone modifications. This results in epigenetic gene silencing of FMR1 presumably by a multi-stage, developmentally regulated process. The timing of FMR1 hypermethylation and transcription silencing is still hotly debated. There is evidence that hypermethylation varies considerably between and within the tissues of patients as well as during fetal development, thus supporting the view that FMR1 silencing is a post-zygotic event that is developmentally structured. On the other hand, it may be established in the female germ line and transmitted to the fetus as an integral part of the mutation. This short review summarizes the data collected to date concerning the timing of FMR1 epigenetic gene silencing and reassess the evidence in favor of the theory that gene inactivation takes place by a developmentally regulated process around the 10th week of gestation.
			KEYWORDS:
			CGG expansion; DNA methylation; FMR1; Fragile X syndrome; epigenetic gene silencing
			PMID: 29467618 PMCID: PMC5808132 DOI: 10.3389/fnmol.2018.00031

	===How common are challenging behaviours amongst individuals with Fragile X Syndrome? A systematic review===		===How common are challenging behaviours amongst individuals with Fragile X Syndrome? A systematic review===

Z8600021 at 22:44, 13 March 2018

2018-03-13T22:44:26Z

← Older revision		Revision as of 09:44, 14 March 2018
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			==2018==

			===How common are challenging behaviours amongst individuals with Fragile X Syndrome? A systematic review===
			Res Dev Disabil. 2018 Mar 7. pii: S0891-4222(18)30047-7. doi: 10.1016/j.ridd.2018.02.020. [Epub ahead of print]

			Hardiman RL1, McGill P2.

			Abstract
			Fragile X Syndrome (FXS) appears to be associated with an increased risk for engaging in challenging behaviour, particularly self-injury, relative to those with mixed aetiology learning disabilities. Such behavioural issues are reported to be of high concern for those providing support. As such, this systematic review aimed to gain further epidemiological data regarding challenging behaviours in individuals with FXS, including: self-injurious behaviour (SIB), hand-biting as a specific topography of SIB, aggression and property destruction. Twenty eight manuscripts were identified which reported the prevalence of a relevant topography of behaviour, with widely varying prevalence estimates. Weighted averages of the prevalence of behaviours were calculated across studies. Comparison of proportions revealed significant gender differences and differences in the prevalence of types of behaviour. It is hoped that this comprehensive overview of data on this clinically significant topic will help to inform and drive future investigation to understand and provide effective intervention for the benefit of those with FXS.
			KEYWORDS:
			Aggression; Behavioural phenotypes; Challenging behaviour; Fragile X Syndrome; Genetic syndromes; Intellectual disability; Learning disability; Problem behaviour; Property destruction; Self injurious behaviour
			PMID: 29525058 DOI: 10.1016/j.ridd.2018.02.020

	==2014==		==2014==

Z8600021 at 00:12, 15 August 2014

2014-08-15T00:12:34Z

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	Klusek J1, Martin GE, Losh M.		Klusek J1, Martin GE, Losh M.
	~~Author information~~

	Abstract		Abstract

	BACKGROUND:		BACKGROUND:
	Prior research suggests that 60-74% of males and 16-45% of females with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD) in research settings. However, relatively little is known about the rates of clinical diagnoses in FXS and whether such diagnoses are consistent with those performed in a research setting using gold standard diagnostic tools.		Prior research suggests that 60-74% of males and 16-45% of females with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD) in research settings. However, relatively little is known about the rates of clinical diagnoses in FXS and whether such diagnoses are consistent with those performed in a research setting using gold standard diagnostic tools.
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	PMID 24528851		PMID 24528851

			==2013==


			===Nuclear Fragile X Mental Retardation Protein is localized to Cajal bodies===
			PLoS Genet. 2013 Oct;9(10):e1003890. doi: 10.1371/journal.pgen.1003890. Epub 2013 Oct 31.

			Dury AY1, El Fatimy R, Tremblay S, Rose TM, Côté J, De Koninck P, Khandjian EW.

			Abstract

			Fragile X syndrome is caused by loss of function of a single gene encoding the Fragile X Mental Retardation Protein (FMRP). This RNA-binding protein, widely expressed in mammalian tissues, is particularly abundant in neurons and is a component of messenger ribonucleoprotein (mRNP) complexes present within the translational apparatus. The absence of FMRP in neurons is believed to cause translation dysregulation and defects in mRNA transport essential for local protein synthesis and for synaptic development and maturation. A prevalent model posits that FMRP is a nucleocytoplasmic shuttling protein that transports its mRNA targets from the nucleus to the translation machinery. However, it is not known which of the multiple FMRP isoforms, resulting from the numerous alternatively spliced FMR1 transcripts variants, would be involved in such a process. Using a new generation of anti-FMRP antibodies and recombinant expression, we show here that the most commonly expressed human FMRP isoforms (ISO1 and 7) do not localize to the nucleus. Instead, specific FMRP isoforms 6 and 12 (ISO6 and 12), containing a novel C-terminal domain, were the only isoforms that localized to the nuclei in cultured human cells. These isoforms localized to specific p80-coilin and SMN positive structures that were identified as Cajal bodies. The Cajal body localization signal was confined to a 17 amino acid stretch in the C-terminus of human ISO6 and is lacking in a mouse Iso6 variant. As FMRP is an RNA-binding protein, its presence in Cajal bodies suggests additional functions in nuclear post-transcriptional RNA metabolism. Supporting this hypothesis, a missense mutation (I304N), known to alter the KH2-mediated RNA binding properties of FMRP, abolishes the localization of human FMRP ISO6 to Cajal bodies. These findings open unexplored avenues in search for new insights into the pathophysiology of Fragile X Syndrome.

			PMID 24204304
	==2012==		==2012==

Z8600021 at 23:18, 20 February 2014

2014-02-20T23:18:31Z

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	==2014==		==2014==

			===Resting-state EEG oscillatory dynamics in fragile x syndrome: abnormal functional connectivity and brain network organization===

			PLoS One. 2014 Feb 11;9(2):e88451. doi: 10.1371/journal.pone.0088451. eCollection 2014.

			van der Molen MJ1, Stam CJ2, van der Molen MW3.
			Author information

			Abstract

			Disruptions in functional connectivity and dysfunctional brain networks are considered to be a neurological hallmark of neurodevelopmental disorders. Despite the vast literature on functional brain connectivity in typical brain development, surprisingly few attempts have been made to characterize brain network integrity in neurodevelopmental disorders. Here we used resting-state EEG to characterize functional brain connectivity and brain network organization in eight males with fragile X syndrome (FXS) and 12 healthy male controls. Functional connectivity was calculated based on the phase lag index (PLI), a non-linear synchronization index that is less sensitive to the effects of volume conduction. Brain network organization was assessed with graph theoretical analysis. A decrease in global functional connectivity was observed in FXS males for upper alpha and beta frequency bands. For theta oscillations, we found increased connectivity in long-range (fronto-posterior) and short-range (frontal-frontal and posterior-posterior) clusters. Graph theoretical analysis yielded evidence of increased path length in the theta band, suggesting that information transfer between brain regions is particularly impaired for theta oscillations in FXS. These findings are discussed in terms of aberrant maturation of neuronal oscillatory dynamics, resulting in an imbalance in excitatory and inhibitory neuronal circuit activity.

			PMID 24523898

	===Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome===		===Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome===

Z8600021 at 23:13, 20 February 2014

2014-02-20T23:13:18Z

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			==2014==

			===Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome===

			J Intellect Disabil Res. 2014 Feb 17. doi: 10.1111/jir.12121. [Epub ahead of print]

			Klusek J1, Martin GE, Losh M.
			Author information

			Abstract
			BACKGROUND:
			Prior research suggests that 60-74% of males and 16-45% of females with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD) in research settings. However, relatively little is known about the rates of clinical diagnoses in FXS and whether such diagnoses are consistent with those performed in a research setting using gold standard diagnostic tools.
			METHOD:
			This study explored whether boys and girls with FXS met criteria for ASD in a research setting using the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R), and then compared these data with the frequency of parent-reported clinical diagnoses. We also examined child and family characteristics as potential diagnostic predictors across settings. Participants included 35 females and 51 males with FXS (mean age: 10 years), who were from Eastern and Midwestern regions of the USA.
			RESULTS:
			About half of the children met criteria for ASD on either the ADOS or ADI-R, with ASD occurring three times more frequently in males than females (∼75% vs. ∼25%). In contrast, ∼25% of participants of both genders had received a clinical diagnosis of ASD. While cognitive and language skills predicted diagnostic outcome on the ADOS and ADI-R, these skills did not predict clinical diagnoses. Executive functions predicted clinical diagnoses, but not diagnoses per the ADOS or ADI-R.
			CONCLUSIONS:
			ASD in FXS may be under-diagnosed in clinical/educational settings, which raises questions regarding access to ASD-related services.
			© 2014 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.
			KEYWORDS:
			ADI-R, ADOS, autism, autism spectrum disorder, comorbidity, fragile X syndrome

			PMID 24528851

	==2012==		==2012==

Z8600021: /* 2009 */

2012-07-20T06:04:55Z

2009

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	===A Mouse Model of the Human Fragile X Syndrome I304N Mutation===		===A Mouse Model of the Human Fragile X Syndrome I304N Mutation===

			PLoS Genet. 2009 Dec;5(12):e1000758. Epub 2009 Dec 11.

	~~PLoS Genet. 2009 December; 5(12): e1000758~~.		Zang JB, Nosyreva ED, Spencer CM, Volk LJ, Musunuru K, Zhong R, Stone EF, Yuva-Paylor LA, Huber KM, Paylor R, Darnell JC, Darnell RB.
	~~Published online 2009 December 11. doi: 10.1371/journal~~.~~pgen.1000758~~		Source
	~~PMCID: PMC2779495~~		Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA.

			Abstract

			The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder.
			PMID: 20011099

	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779495		http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779495

	http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000758		http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000758

Z8600021 at 06:03, 20 July 2012

2012-07-20T06:03:09Z

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	PMID 21423665		PMID 21423665

			==2009==

			===A Mouse Model of the Human Fragile X Syndrome I304N Mutation===


			PLoS Genet. 2009 December; 5(12): e1000758.
			Published online 2009 December 11. doi: 10.1371/journal.pgen.1000758
			PMCID: PMC2779495


			http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779495

			http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000758

Z8600021 at 05:55, 20 July 2012

2012-07-20T05:55:22Z

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	PMID 22750206		PMID 22750206
			==2011==

			===Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities!===

			PLoS Genet. 2011 Mar;7(3):e1002018. Epub 2011 Mar 10.

			Pearson CE.
			Source
			Program of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. cepearson.sickkids@gmail.com

			Abstract

			Diseases associated with unstable repetitive elements in the DNA, RNA, and amino acids have consistently revealed scientific surprises. Most diseases are caused by expansions of trinucleotide repeats, which ultimately lead to diseases like Huntington's disease, myotonic dystrophy, fragile X syndrome, and a series of spinocerebellar ataxias. These repeat mutations are dynamic, changing through generations and within an individual, and the repeats can be bi-directionally transcribed. Unsuspected modes of pathogenesis involve aberrant loss of protein expression; aberrant over-expression of non-mutant proteins; toxic-gain-of-protein function through expanded polyglutamine tracts that are encoded by expanded CAG tracts; and RNA-toxic-gain-of-function caused by transcripts harboring expanded CUG, CAG, or CGG tracts. A recent advance reveals that RNA transcripts with expanded CAG repeats can be translated in the complete absence of a starting ATG, and this Repeat Associated Non-ATG translation (RAN-translation) occurs across expanded CAG repeats in all reading frames (CAG, AGC, and GCA) to produce homopolymeric proteins of long polyglutamine, polyserine, and polyalanine tracts. Expanded CTG tracts expressing CUG transcripts also show RAN-translation occurring in all three frames (CUG, UGC, and GCU), to produce polyleucine, polycysteine, and polyalanine. These RAN-translation products can be toxic. Thus, one unstable (CAG)•(CTG) DNA can produce two expanded repeat transcripts and homopolymeric proteins with reading frames (the AUG-directed polyGln and six RAN-translation proteins), yielding a total of potentially nine toxic entities. The occurrence of RAN-translation in patient tissues expands our horizons of modes of disease pathogenesis. Moreover, since RAN-translation counters the canonical requirements of translation initiation, many new questions are now posed that must be addressed. This review covers RAN-translation and some of the pertinent questions.

			PMID 21423665

Z8600021: /* Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome */

2012-07-20T05:45:36Z

Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome

← Older revision		Revision as of 16:45, 20 July 2012
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	http://www.hindawi.com/journals/np/2012/104796/		http://www.hindawi.com/journals/np/2012/104796/


			===Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse===
			Neuroscience. 2012 Jun 28. [Epub ahead of print]

			Gocel J, Larson J.
			Source
			Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, United States.

			Abstract

			Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1-KO mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-d-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs.
			Copyright © 2012. Published by Elsevier Ltd.

			PMID 22750206

Z8600021 at 05:43, 20 July 2012

2012-07-20T05:43:47Z

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	PMID 22797890		PMID 22797890


			===Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome===
			Neural Plast. 2012;2012:104796. Epub 2012 Jun 20.

			Kelley K, Chang SJ, Lin SL.
			Source

			Division of Regenerative Medicine, WJWU & LYNN Institute for Stem Cell Research, 12145 Mora Drive, STE6, Santa Fe Springs, CA 90670, USA.

			Abstract

			The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed by Dicer endoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of the FMR1 5'-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptional FMR1 gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, while FMR1 inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

			PMID 22779005

			http://www.hindawi.com/journals/np/2012/104796/