Fragile X spectrum disorders

Lozano, Reymundo; Rosero, Carolina; Hagerman, Randi J

doi:10.5582/irdr.2014.01022

Cited by 147 publications

(107 citation statements)

References 159 publications

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“…Patients with FXS have cognitive and behavioral deficits, anxiety, and a susceptibility to epilepsy (Jacquemont et al, 2007;Lozano et al, 2014). At the cellular level, FXS neurons have an increased number of dendritic spines that appear long, thin, and tortuous (Hinton et al, 1991;Irwin et al, 2001).…”

Section: Introductionmentioning

confidence: 97%

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Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

Pasciuto

Ahmed

Wahle

et al. 2015

Neuron

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The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.

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Section: Introductionmentioning

confidence: 97%

“…FXS is the most common form of inherited intellectual disability and about 30% of FXS children meet the criteria for ASD (Jacquemont et al, 2007;Lozano et al, 2014). Patients with FXS have cognitive and behavioral deficits, anxiety, and a susceptibility to epilepsy (Jacquemont et al, 2007;Lozano et al, 2014).…”

Section: Introductionmentioning

confidence: 97%

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

Pasciuto

Ahmed

Wahle

et al. 2015

Neuron

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“…Fragile X Syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism, affecting 1 out of every 4,000 males and 1 out of every 7,000 females (Lozano et al ., 2014). FXS is caused by an expansion of a CGG repeat in the 5′-untranslated region of the fragile X mental retardation 1 ( FMR1 ) gene which results in silencing of the gene (Pieretti et al ., 1991).…”

Section: Introductionmentioning

confidence: 99%

Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

Bonasera

Chaudoin

Goulding

et al. 2017

Genes Brain and Behavior

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Fragile X syndrome (FXS) is a common inherited disorder that significantly impacts family and patient day-to-day living across the entire lifespan. The childhood and adolescent behavioral consequences of FXS are well-appreciated. However, there are significantly fewer studies (except those examining psychiatric comorbidities) assessing behavioral phenotypes seen in adults with FXS. Mice engineered with a genetic lesion of Fmr1 recapitulate important molecular and neuroanatomical characteristics of FXS, and provide a means to evaluate adult behavioral phenotypes associated with FXS. We give the first description of baseline behaviors including feeding, drinking, movement, and their circadian rhythms; all observed over 16 consecutive days following extensive environmental habituation in adult Fmr1-KO mutant mice. We find no genotypic changes in mouse food ingestion, feeding patterns, metabolism, or circadian patterns of movement, feeding, and drinking. After habituation, Fmr1-KO mice demonstrate significantly less daily movement during their active phase (the dark cycle). However, Fmr1-KO mice have more bouts of activity during the light cycle compared to wildtypes. In addition, Fmr1-KO mice demonstrate significantly less daily water ingestion during the circadian dark cycle, and this reduction in water intake is accompanied by a decrease in the amount of water ingested per lick. The observed water ingestion and circadian phenotypes noted in Fmr1-KO mice recapitulate known clinical aspects previously described in FXS. The finding of decreased movement in Fmr1-KO mice is novel, and suggests a dissociation between baseline and novelty-evoked activity for Fmr1-KO mice.

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“…2 Affected males typically have more severe phenotypes than females, including autism, intellectual and developmental disability, social anxiety, attention deficit hyperactivity, and other physical malformations. 3,4 Affected pregnancies can be avoided by preimplantation genetic diagnosis (PGD) or terminated after prenatal diagnosis.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Furthermore, PM alleles are unstable and have a strong tendency to expand to FM alleles upon maternal transmission within one generation; therefore, women carrying these alleles have an increased risk of having pregnancies affected with FXS. The high population prevalence of PM alleles (1 in 130-250 females and 1 in 250-810 males 3 ) further increases this risk. Consequently, female sex selection, which is commonly used to avoid X-linked disorders in general, is unsuitable for PGD of FXS because female carrier embryos may be affected.…”

Section: Introductionmentioning

confidence: 99%

Identification of microsatellite markers <1 Mb from the FMR1 CGG repeat and development of a single-tube tetradecaplex PCR panel of highly polymorphic markers for preimplantation genetic diagnosis of fragile X syndrome

Chen

Zhao

Lee

et al. 2016

Genetics in Medicine

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Purpose: To develop a single-tube polymerase chain reaction (PCR) panel of highly polymorphic markers for preimplantation genetic diagnosis (PGD) of fragile X syndrome (FXS).Methods: An in silico search was performed to identify all markers within 1 Mb flanking the FMR1 gene. Selected markers were optimized into a single-tube PCR panel and their polymorphism indices were determined from 272 female samples from three populations. The single-tube assay was also validated on 30 single cells to evaluate its applicability to FXS PGD.Results: Thirteen markers with potentially high polymorphism information content (PIC) and heterozygosity values were selected and optimized into a single-tube PCR panel together with AMELX/Y for gender determination. Analysis of 272 female samples confirmed the high polymorphism (PIC > 0.5) of most markers, with expected and observed heterozygosities ranging from 0.31 to 0.87. More than 99% of individuals were heterozygous for at least three markers, with 95.8% of individuals heterozygous for at least two markers on either side of the FMR1 CGG repeat. Conclusion:The tetradecaplex marker assay can be performed directly on single cells or after whole-genome amplification, thus supporting its use in FXS PGD either as a standalone linkage-based assay or as a complement to FMR1 mutation detection.

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Fragile X spectrum disorders

Cited by 147 publications

References 159 publications

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

Decreased home cage movement and oromotor impairments in adult Fmr1‐KO mice

Identification of microsatellite markers <1 Mb from the FMR1 CGG repeat and development of a single-tube tetradecaplex PCR panel of highly polymorphic markers for preimplantation genetic diagnosis of fragile X syndrome

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