Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by derangements in nervous system especially in cognition and behavior. The present study aims to understand the molecular underpinnings of two subtypes of RTT, classic RTT and Rett-like, and to elucidate common pathways giving rise to common RTT phenotype using genomic and transcriptomic approaches. Mutation screening on selected nuclear genes revealed only MECP2 mutations in a subset of classic RTT patients. MLPA assays and mtDNA screenings were all negative. Genome-wide copy number analysis indicated a novel duplication on X chromosome. Transcriptional profiling revealed blood gene signatures that clearly distinguish classic RTT and RTT-like patients, as well as shared altered pathways in interleukin-4 and NF-κB signaling pathways in both subtypes of the syndrome. To our knowledge, this is the first report on investigating common regulatory mechanisms/signaling pathways that may be relevant to the pathobiology of the "common RTT" phenotype.
"The more recent technology of cytogenomic microarray analysis (CMA) has identified an increasing number of copy number gains and losses present in patients with ASD [Cook and Scherer, 2008; Glessner et al., 2009; Colak et al., 2011] In 2009, Glessner et al. identified seven patients with ASD who had a chromosome 6 copy number loss involving the PARK2 gene region. Control patients did not show this copy number loss. "
[Show abstract][Hide abstract] ABSTRACT: Microdeletions of PARK2 have been reported previously in seven patients with autism spectrum disorder. There are no reports of PARK2 microduplications in this population. Presented are two patients, one with deletion and the other with duplication, both with autism spectrum disorder, though their syndromic phenotypes vary. The deletion patient is cognitively normal and ectomorphic: the duplication patient is cognitively impaired, underweight and short. Further, the microduplication patient has demonstrated adverse medication reactions to psychotropic medications active in the dopamine metabolic pathway: cyclopentolate, lisdexamfetamine, methylphenidate. These patients support an association between PARK2 mutations and autism spectrum disorder and suggest that duplications may be equally causative. It is hypothesized that the disparate patient phenotypes may represent a deletion/duplication syndrome and that the adverse medication reactions may be a pharmacogenetic phenomenon.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2011; 156B(4):413-20. DOI:10.1002/ajmg.b.31176 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa.
We evaluated the affected individuals, all maternally related, using childhood autism rating scale (CARS) and Vineland Adaptive scales, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain, electroencephalography (EEG), electromyography (EMG), muscle biopsy, high-resolution molecular karyotype arrays, Giemsa banding (G-banding) and fluorescent in situ hybridization (FISH) experiments, mitochondrial DNA (mtDNA) sequencing, X-chromosome inactivation study, global gene expression analysis on Epstein-Barr virus (EBV)-transformed lymphoblasts, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR).
We have identified a novel Xq12-q13.3 duplication in an extended family. Clinically normal mothers were completely skewed in favor of the normal chromosome X. Global transcriptional profiling of affected individuals and controls revealed significant alterations of genes and pathways in a pattern consistent with previous microarray studies of autism spectrum disorder patients. Moreover, expression analysis revealed copy number-dependent increased messenger RNA (mRNA) levels in affected patients compared to control individuals. A subset of differentially expressed genes was validated using qRT-PCR.
Xq12-q13.3 duplication is a novel global developmental delay and autism-predisposing chromosomal aberration; pathogenesis of which may be mediated by increased dosage of genes contained in the duplication, including NLGN3, OPHN1, AR, EFNB1, TAF1, GJB1, and MED12.
Annals of Neurology 04/2012; 71(4):498-508. DOI:10.1002/ana.22673 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF-κB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase (IKK)/NF-κB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF-κB-dependent synapse development and remodeling. Here, we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmission and a spatial learning impairment. Synaptic deficits can be restored in adult animals within 1 week by IKK/NF-κB reactivation, indicating a highly dynamic IKK/NF-κB-dependent regulation process. We further identified the insulin-like growth factor 2 gene (Igf2) as a novel IKK/NF-κB target. Exogenous Igf2 was able to restore synapse density and promoted spine maturation in IKK/NF-κB signaling-deficient neurons within 24 h. This process depends on Igf2/Igf2R-mediated MEK/ERK activation. Our findings illustrate a fundamental role of IKK/NF-κB-Igf2-Igf2R signaling in synapse formation and maturation in adult mice, thus providing an intriguing link between the molecular actions of IKK/NF-κB in neurons and the memory enhancement factor Igf2.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(16):5688-703. DOI:10.1523/JNEUROSCI.0111-12.2012 · 6.34 Impact Factor
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