Autism in two females with duplications involving Xp11.22-p11.23

Edens, Anna C; Lyons, Michael J.; Durón, Reyna M.; DuPont, Barbara R.; Holden, Kenton R.

doi:10.1111/j.1469-8749.2010.03909.x

Cited by 22 publications

(22 citation statements)

References 16 publications

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“…Interestingly, GRASP1 is an X-Chromosome gene located at Xp11.23, a region that has been previously associated with ID and autism (Chung et al, 2011; Edens et al, 2011; Giorda et al, 2009). We performed a screen on a cohort of well-characterized male probands (n=400) with ID and a pedigree consistent with X - I inked (XL) inheritance (Wu et al, 2007; Zhang et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors

Chiu

Diering

et al. 2017

Neuron

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Summary Learning depends on experience-dependent modification of synaptic efficacy and neuronal connectivity in the brain. We provide direct evidence for physiological roles of the recycling endosome protein GRASP1 in glutamatergic synapse function and animal behavior. Mice lacking GRASP1 showed abnormal excitatory synapse number, synaptic plasticity and hippocampal-dependent learning and memory due to a failure in learning-induced synaptic AMPAR incorporation. We identified two GRASP1 point mutations from intellectual disability (ID) patients that showed convergent disruptive effects on AMPAR recycling and glutamate uncaging-induced structural and functional plasticity. Wild-type GRASP1, but not ID mutants, rescues spine loss in hippocampal CA1 neurons of Grasp1 knockout mice. Together, these results demonstrate a requirement for normal recycling endosome function in AMPAR-dependent synaptic function and neuronal connectivity in vivo, and suggest a potential role for GRASP1 in the pathophysiology of human cognitive disorders.

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Section: Resultsmentioning

confidence: 99%

GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors

Chiu

Diering

et al. 2017

Neuron

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“…Clinical and genetic findings in the present Patients 1–5 and previously reported patients with overlapping, molecularly characterized duplications are summarized in Table and Figure . Of particular interest is a recurrent microduplication Xp11.22‐p11.23 of about 4.5 Mb reported previously in 11 female patients from eight families [Giorda et al, ; Chung et al, ; Family 1, Family 2, Case 4, Case 8, Case 9; Marshall et al, ; Case SK0306–004; Edens et al, ; Case 2] as well as a larger duplication of about 6 Mb in a further female which shares the distal breakpoint but has a different proximal breakpoint [Giorda et al, ; Case 5]. In 10 of these 12 females the XI pattern was analyzed and 7/10 cases showed a skewed inactivation (defined as >80% of one X‐Chromosome), all of them with preferential inactivation of the normal X. Giorda et al found a comparable phenotype in the patients known up to 2009 [Giorda et al, ] consisting of DD/ID, a particular speech impairment, often EEG anomalies (typically continuous spike waves during slow sleep and/or rolandic‐like spikes), and, in addition, overweight in half of the cases, and reported on a similar phenotype in two males with the recurrent duplication.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, small duplications of the proximal short arm of the X chromosome, in particular duplications encompassing Xp11.23, have been reported to be associated with neurodevelopmental disorders both in males and females [Bonnet et al, ; Froyen et al, ; Marshall et al, ; Monnot et al, ; Giorda et al, ; Holden et al, ; Chung et al, ; Edens et al, ; El‐Hattab et al, ]. Surprisingly, and in contrast to previously described larger duplications in Xp with selective inactivation of the aberrant X‐chromosome and a commonly normal phenotype in most carrier women [Matsuo et al, ], females with microduplications including Xp11.23 repeatedly showed preferential inactivation of the normal X‐chromosome.…”

Section: Introductionmentioning

confidence: 98%

Duplication Xp11.22‐p14 in females: Does X‐inactivation help in assessing their significance?

Evers

Mitter

Strobl‐Wildemann

et al. 2015

American J of Med Genetics Pt A

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In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic.

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“…These associated disorders are particularly interesting since we have identified RORA deficiency (specifically, reduced expression) in the phenotypic subtype of ASD associated with severe language impairment [13]. Using chromosome microarray analysis, Edens and colleagues reported duplications involving Xp11.22-p11.23, a region where HSD17B10 gene is located, in two females with autism and epilepsy [90]. …”

Section: Discussionmentioning

confidence: 99%

Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder

2013

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BackgroundWe have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as in the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans.MethodsHere we identify transcriptional targets of RORA in human neuronal cells on a genome-wide level using chromatin immunoprecipitation (ChIP) with an anti-RORA antibody followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then validated by an independent ChIP followed by quantitative PCR analysis. To further demonstrate that reduced RORA expression results in reduced transcription of RORA targets, we determined the expression levels of the selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression.ResultsThe ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 2,764 genomic locations corresponding to promoter regions of 2,544 genes across the human genome. Gene ontology analysis of this dataset of genes that are potentially directly regulated by RORA1 reveals statistically significant enrichment in biological functions negatively impacted in individuals with ASD, including neuronal differentiation, adhesion and survival, synaptogenesis, synaptic transmission and plasticity, and axonogenesis, as well as higher level functions such as development of the cortex and cerebellum, cognition, memory, and spatial learning. Independent ChIP-quantitative PCR analyses confirm binding of RORA1 to promoter regions of selected ASD-associated genes, including A2BP1, CYP19A1, ITPR1, NLGN1, and NTRK2, whose expression levels (in addition to HSD17B10) are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD.ConclusionsFindings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these ASD-relevant genes as well as their associated pathways and functions which, in turn, may contribute to the underlying pathobiology of ASD.

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Autism in two females with duplications involving Xp11.22-p11.23

Cited by 22 publications

References 16 publications

GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors

GRASP1 Regulates Synaptic Plasticity and Learning through Endosomal Recycling of AMPA Receptors

Duplication Xp11.22‐p14 in females: Does X‐inactivation help in assessing their significance?

Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder

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