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Single-Nucleotide Mutations in FMR1 Reveal Novel Functions and Regulatory Mechanisms of the Fragile X Syndrome Protein FMRP.

January 29, 2016 - 8:54am

Single-Nucleotide Mutations in FMR1 Reveal Novel Functions and Regulatory Mechanisms of the Fragile X Syndrome Protein FMRP.

J Exp Neurosci. 2015;9(Suppl 2):35-41

Authors: Suhl JA, Warren ST

Abstract
Fragile X syndrome is a monogenic disorder and a common cause of intellectual disability. Despite nearly 25 years of research on FMR1, the gene underlying the syndrome, very few pathological mutations other than the typical CGG-repeat expansion have been reported. This is in contrast to other X-linked, monogenic, intellectual disability disorders, such as Rett syndrome, where many point mutations have been validated as causative of the disorder. As technology has improved and significantly driven down the cost of sequencing, allowing for whole genes to be sequenced with relative ease, in-depth sequencing studies on FMR1 have recently been performed. These studies have led to the identification of novel variants in FMR1, where some of which have been functionally evaluated and are likely pathogenic. In this review, we discuss recently identified FMR1 variants, the ways these novel variants cause dysfunction, and how they reveal new regulatory mechanisms and functionalities of the gene.

PMID: 26819560 [PubMed]

NKCC1-Mediated GABAergic Signaling Promotes Postnatal Cell Death in Neocortical Cajal-Retzius Cells.

January 29, 2016 - 8:54am

NKCC1-Mediated GABAergic Signaling Promotes Postnatal Cell Death in Neocortical Cajal-Retzius Cells.

Cereb Cortex. 2016 Jan 26;

Authors: Blanquie O, Liebmann L, Hübner CA, Luhmann HJ, Sinning A

Abstract
During early development, a substantial proportion of central neurons undergoes programmed cell death. This activity-dependent process is essential for the proper structural and functional development of the brain. To uncover cell type-specific differences in the regulation of neuronal survival versus apoptosis, we studied activity-regulated cell death in Cajal-Retzius neurons (CRNs) and the overall neuronal population in the developing mouse cerebral cortex. CRNs in the upper neocortical layer represent an early-born neuronal population, which is important for cortical development and largely disappears by apoptosis during neonatal stages. In contrast to the overall neuronal population, activity blockade with tetrodotoxin improved survival of CRNs in culture. Activation of GABAA receptors also blocked spontaneous activity and caused overall cell death including apoptosis of CRNs. Blockade of the Na-K-Cl transporter NKCC1 in vitro or its genetic deletion in vivo rescued CRNs from apoptosis. This effect was mediated by blockade of the p75(NTR) receptor signaling pathway. In summary, we discovered a novel developmental death pathway mediated by NKCC1, via GABAA receptor-mediated membrane depolarization and p75(NTR) signaling in CRNs. This pathway controls apoptosis of CRNs and may be critically involved in neurodevelopmental disorders such as autism and schizophrenia.

PMID: 26819276 [PubMed - as supplied by publisher]

Progress in autism and related disorders of brain development.

January 28, 2016 - 8:26am
Related Articles

Progress in autism and related disorders of brain development.

Lancet Neurol. 2015 Nov;14(11):1069-70

Authors: Berg AT, Dobyns WB

PMID: 25891008 [PubMed - indexed for MEDLINE]

Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

January 28, 2016 - 8:26am
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Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

PLoS One. 2015;10(3):e0118627

Authors: Kazim SF, Cardenas-Aguayo Mdel C, Arif M, Blanchard J, Fayyaz F, Grundke-Iqbal I, Iqbal K

Abstract
Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

PMID: 25769033 [PubMed - indexed for MEDLINE]

Gene hunting in autism spectrum disorder: on the path to precision medicine.

January 27, 2016 - 8:12am
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Gene hunting in autism spectrum disorder: on the path to precision medicine.

Lancet Neurol. 2015 Nov;14(11):1109-20

Authors: Geschwind DH, State MW

Abstract
Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment.

PMID: 25891009 [PubMed - indexed for MEDLINE]

Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2.

January 26, 2016 - 7:57am

Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2.

Nature. 2016 Jan 25;

Authors: Liu Z, Li X, Zhang JT, Cai YJ, Cheng TL, Cheng C, Wang Y, Zhang CC, Nie YH, Chen ZF, Bian WJ, Zhang L, Xiao J, Lu B, Zhang YF, Zhang XD, Sang X, Wu JJ, Xu X, Xiong ZQ, Zhang F, Yu X, Gong N, Zhou WH, Sun Q, Qiu Z

Abstract
Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.

PMID: 26808898 [PubMed - as supplied by publisher]

A structured assessment of motor function and behavior in patients with Kleefstra Syndrome.

January 26, 2016 - 7:57am

A structured assessment of motor function and behavior in patients with Kleefstra Syndrome.

Eur J Med Genet. 2016 Jan 22;

Authors: Schmidt S, Nag HE, Hunn BS, Houge G, Hoxmark LB

Abstract
The present study aimed to further our understanding of Kleefstra syndrome, especially regarding motor function and behavioral characteristics. In total, four males and four females between two and 27 years of age with a genetically confirmed diagnosis of Kleefstra syndrome and their parents participated in this study. Four patients had 9q34.3 deletions that caused Euchromatin Histone Methyl Transferase 1 (EHMT1) haplo-insufficiency, and four patients harbored EHMT1 mutations. The motor function was evaluated via systematic observation. Standardized assessments such as the Vineland Adapted Behavior Scales II (VABS II), the Social Communication Questionnaire (SCQ) and the Child or Adult Behavior Checklist (CBCL, ABCL) were used for the behavioral assessment. All patients showed a delayed developmental status. Muscular hypotonia and its manifestations were present in all patients, regardless of their age. The mean values for all VABS II domains (communication, socialization, daily living skills, and motor skills) were significantly lower than the mean of the reference population (p < 0.001), but similar to other rare intellectual disabilities such as Smith-Magenis syndrome and Angelman syndrome. The results from the SCQ indicated that all patient values exceeded the cut-off value, suggesting the possibility of autism spectrum disorder. The behavioral and emotional problems assessed by CBCL and ABCL were less frequent. In conclusion, patients with Kleefstra syndrome present with a broad range of clinical problems in all age groups and are therefore in need of a multidisciplinary follow-up also after their transition into adulthood.

PMID: 26808425 [PubMed - as supplied by publisher]

Low load for disruptive mutations in autism genes and their biased transmission.

January 26, 2016 - 7:57am
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Low load for disruptive mutations in autism genes and their biased transmission.

Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):E5600-7

Authors: Iossifov I, Levy D, Allen J, Ye K, Ronemus M, Lee YH, Yamrom B, Wigler M

Abstract
We previously computed that genes with de novo (DN) likely gene-disruptive (LGD) mutations in children with autism spectrum disorders (ASD) have high vulnerability: disruptive mutations in many of these genes, the vulnerable autism genes, will have a high likelihood of resulting in ASD. Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure. An immediate prediction is that these genes will have a lower LGD load than typical genes in the human gene pool. We confirm this hypothesis in an explicit test by measuring the load of disruptive mutations in whole-exome sequence databases from two cohorts. We use information about mutational load to show that lower and higher intelligence quotients (IQ) affected individuals can be distinguished by the mutational load in their respective gene targets, as well as to help prioritize gene targets by their likelihood of being autism genes. Moreover, we demonstrate that transmission of rare disruptions in genes with a lower LGD load occurs more often to affected offspring; we show transmission originates most often from the mother, and transmission of such variants is seen more often in offspring with lower IQ. A surprising proportion of transmission of these rare events comes from genes expressed in the embryonic brain that show sharply reduced expression shortly after birth.

PMID: 26401017 [PubMed - indexed for MEDLINE]

Autism and behavior in adult patients with Dravet syndrome (DS).

January 26, 2016 - 7:57am
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Autism and behavior in adult patients with Dravet syndrome (DS).

Epilepsy Behav. 2015 Jun;47:11-6

Authors: Berkvens JJ, Veugen I, Veendrick-Meekes MJ, Snoeijen-Schouwenaars FM, Schelhaas HJ, Willemsen MH, Tan IY, Aldenkamp AP

Abstract
INTRODUCTION: Autism and behavioral characteristics in adults with Dravet syndrome (DS) have rarely been systematically studied.
METHOD: Three scales were used to assess the outcomes of DS in adulthood in terms of autism and behavior. All the adult patients with DS, nine male and four female, aged between 18 and 60 years, living at the Epilepsy Center Kempenhaeghe in The Netherlands were included in the study. In addition, the past medical history of each patient was systematically screened for diagnoses like autism, Pervasive Development Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD), hyperactivity, Attention Deficit Hyperactivity Disorder (ADHD), and self-mutilation. Information concerning past and current use of psychoactive drugs was also evaluated.
RESULTS: Eight patients (61.5%) were classified as having autism spectrum disorder (ASD) according to the AVZ-R or according to the medical record. Self-mutilation was seen in four patients (30.8%), hyperactivity in none. Three patients (23.1%) currently used psychoactive drugs.
CONCLUSION: Autism spectrum disorders persist in adult patients with DS, while certain characteristics associated with behavioral problems, such as hyperactivity or use of psychoactive medication, seem to be less prominent than in childhood.

PMID: 26005841 [PubMed - indexed for MEDLINE]

Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.

January 26, 2016 - 7:57am
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Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.

Neuropsychopharmacology. 2015 Jun;40(7):1569-79

Authors: Aida T, Yoshida J, Nomura M, Tanimura A, Iino Y, Soma M, Bai N, Ito Y, Cui W, Aizawa H, Yanagisawa M, Nagai T, Takata N, Tanaka KF, Takayanagi R, Kano M, Götz M, Hirase H, Tanaka K

Abstract
An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLAST(CreERT2/+)/GLT1(flox/flox), iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.

PMID: 25662838 [PubMed - indexed for MEDLINE]

Language impairment and dyslexia genes influence language skills in children with autism spectrum disorders.

January 26, 2016 - 7:57am
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Language impairment and dyslexia genes influence language skills in children with autism spectrum disorders.

Autism Res. 2015 Apr;8(2):229-34

Authors: Eicher JD, Gruen JR

Abstract
Language and communication development is a complex process influenced by numerous environmental and genetic factors. Many neurodevelopment disorders include deficits in language and communication skills in their diagnostic criteria, including autism spectrum disorders (ASD), language impairment (LI), and dyslexia. These disorders are polygenic and complex with a significant genetic component contributing to each. The similarity of language phenotypes and comorbidity of these disorders suggest that they may share genetic contributors. To test this, we examined the association of genes previously implicated in dyslexia, LI, and/or language-related traits with language skills in children with ASD. We used genetic and language data collected in the Autism Genome Research Exchange (AGRE) and Simons Simplex Collection (SSC) cohorts to perform a meta-analysis on performance on a receptive vocabulary task. There were associations with LI risk gene ATP2C2 and dyslexia risk gene MRPL19. Additionally, we found suggestive evidence of association with CMIP, GCFC2, KIAA0319L, the DYX2 locus (ACOT13, GPLD1, and FAM65B), and DRD2. Our results show that LI and dyslexia genes also contribute to language traits in children with ASD. These associations add to the growing literature of generalist genes that contribute to multiple related neurobehavioral traits. Future studies should examine whether other genetic contributors may be shared among these disorders and how risk variants interact with each other and the environment to modify clinical presentations.

PMID: 25448322 [PubMed - indexed for MEDLINE]

Clinical Correlates of Hoarding With and Without Comorbid Obsessive-Compulsive Symptoms in a Community Pediatric Sample.

January 24, 2016 - 7:35am

Clinical Correlates of Hoarding With and Without Comorbid Obsessive-Compulsive Symptoms in a Community Pediatric Sample.

J Am Acad Child Adolesc Psychiatry. 2016 Feb;55(2):114-121.e2

Authors: Burton CL, Crosbie J, Dupuis A, Mathews CA, Soreni N, Schachar R, Arnold PD

Abstract
OBJECTIVE: We assessed the prevalence and clinical correlates of hoarding, with and without obsessive-compulsive (OC) symptoms, in a community-based pediatric sample.
METHOD: We measured hoarding and OC symptoms using the Toronto Obsessive-Compulsive Scale (TOCS) in 16,718 youth aged 6 to 17 years in the community. We classified participants with high and low symptom counts for hoarding and OC into 4 groups: hoarding+OC; hoarding-only; OC-only; and control (no OC or hoarding symptoms). We compared these 4 groups on parent- or self-reported medical and psychiatric conditions, anxiety symptoms measured with the Child Behavior Checklist (CBCL), and attention-deficit/hyperactivity disorder (ADHD) symptoms measured with the Strengths and Weaknesses of Attention-Deficit/Hyperactivity Disorder Symptoms and Normal Behavior Scale (SWAN).
RESULTS: Almost 10% of participants were in the high hoarding group. Of these participants, 40% did not fall into the high OC group. The prevalence of reported psychiatric disorders (e.g., ADHD, autism spectrum disorder, obsessive-compulsive disorder) was greater in the hoarding (hoarding+OC and hoarding-only) and OC groups (hoarding+OC and OC-only) than in the nonhoarding (OC-only and control) and non-OC groups (hoarding-only and control), respectively. ADHD, specifically inattentive, symptoms were more common in the hoarding-only than in the OC-only group while anxiety symptoms were more common in the OC-only than in the hoarding-only group.
CONCLUSION: In a community pediatric sample, hoarding symptoms occurred in both the presence and absence of obsessive-compulsive symptoms. Hoarding symptoms alone had some unique clinical correlates, in particular, more inattentive ADHD symptoms and fewer anxiety symptoms. These findings suggest that hoarding is distinct from OC traits in youth.

PMID: 26802778 [PubMed - as supplied by publisher]

Autism Spectrum Disorders and Other Mental Health Problems: Exploring Etiological Overlaps and Phenotypic Causal Associations.

January 24, 2016 - 7:35am

Autism Spectrum Disorders and Other Mental Health Problems: Exploring Etiological Overlaps and Phenotypic Causal Associations.

J Am Acad Child Adolesc Psychiatry. 2016 Feb;55(2):106-113.e4

Authors: Tick B, Colvert E, McEwen F, Stewart C, Woodhouse E, Gillan N, Hallett V, Lietz S, Garnett T, Simonoff E, Ronald A, Bolton P, Happé F, Rijsdijk F

Abstract
OBJECTIVE: Recent studies have highlighted the impact of coexisting mental health problems in autism spectrum disorders (ASD). No twin studies to date have reported on individuals meeting diagnostic criteria of ASD. This twin study reports on the etiological overlap between the diagnosis of ASD and emotional symptoms, hyperactivity, and conduct problems measured with the Strengths and Difficulties Questionnaire.
METHOD: Genetic and environmental influences on the covariance between ASD and coexisting problems were estimated, in line with the correlated risks model prediction. Phenotypic causality models were also fitted to explore alternative explanations of comorbidity: namely, that coexisting problems are the result of or result in ASD symptoms; that they increase recognition of ASD; or that they arise due to an over-observation bias/confusion when differentiating between phenotypes.
RESULTS: More than 50% of twins with broad spectrum/ASD met the borderline/abnormal levels cut-off criteria for emotional symptoms or hyperactivity, and approximately 25% met these criteria for the 3 reported problems. In comparison, between 13% and 16% of unaffected twins scored above the cut-offs. The phenotypic correlation between ASD and emotional symptoms was explained entirely by genetic influences and accompanied by a moderate genetic correlation (0.42). The opposite was true for the overlap with conduct problems, as nonshared-environmental factors had the strongest impact. For hyperactivity, the best-fitting model suggested a unidirectional phenotypic influence of hyperactivity on ASD.
CONCLUSION: Our findings suggest a possible effect of hyperactivity on identification of ASD. The lack of genetic influences on conduct problems-ASD overlap further supports the genetic independence of these 2 phenotypes. Finally, the co-occurrence of emotional symptoms in ASD, compared to other co-occurring problems, is completely explained by common genetic effects.

PMID: 26802777 [PubMed - as supplied by publisher]

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

January 23, 2016 - 7:34am

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

PLoS One. 2016;11(1):e0146797

Authors: Zhang Y, Hodgson NW, Trivedi MS, Abdolmaleky HM, Fournier M, Cuenod M, Do KQ, Deth RC

Abstract
Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders.

PMID: 26799654 [PubMed - as supplied by publisher]

A Novel Recurrent Breakpoint Responsible for Rearrangements in the Williams-Beuren Region.

January 23, 2016 - 7:34am
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A Novel Recurrent Breakpoint Responsible for Rearrangements in the Williams-Beuren Region.

Cytogenet Genome Res. 2015;146(3):181-6

Authors: Plaja A, Castells N, Cueto-González AM, del Campo M, Vendrell T, Lloveras E, Izquierdo L, Borregan M, Rodríguez-Santiago B, Carrió A, Miró R, Tizzano E

Abstract
Copy number variants (CNVs) of the Williams-Beuren syndrome (WBS) 7q11.23 region are responsible for neurodevelopmental disorders with multisystem involvement and variable expressivity. We found 2 patients with a deletion and 1 patient with a duplication in this region sharing a common breakpoint located between the LIMK1 and EIF4H(WBSCR1) genes. One patient had a WBS phenotype, although testing with a commercially available FISH assay was negative for the deletion. A further test using array CGH showed an atypical WBS region deletion. The second patient showed global developmental delay, speech delay and poor motor skills with a deletion outside the WBS region. The third patient had manifestations compatible with an autism spectrum disorder showing a duplication in the WBS region. Our findings point to the existence of a previously unrecognized recurrent breakpoint responsible for rearrangements in the WBS region. Given that most commercial FISH assays include probes flanking this novel breakpoint, further testing with array CGH should be performed in patients with WBS and negative FISH results.

PMID: 26382598 [PubMed - indexed for MEDLINE]

Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine.

January 23, 2016 - 7:34am
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Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine.

Expert Rev Proteomics. 2015 Jun;12(3):317-28

Authors: Katoh M

Abstract
ASXL1, ASXL2 and ASXL3 are epigenetic scaffolds for BAP1, EZH2, NCOA1, nuclear receptors and WTIP. Here, functional proteomics of the ASXL family members are reviewed with emphasis on mutation spectra, the ASXM2 domain and the plant homeodomain (PHD) finger. Copy number gains of ASXL1 occur in chromosome 20q11.2 duplication syndrome and cervical cancer. Truncation mutations of ASXLs occur in autism, Bohring-Opitz and related syndromes, hematological malignancies and solid tumors, such as prostate cancer, breast cancer and high-grade glioma, which are gain- or loss-of-function mutations. The ASXM2 domain is a binding module for androgen receptor and estrogen receptor α, while the PHD finger is a ligand of WTIP LIM domains and a putative chromatin-binding module. Phylogenetic analyses of 139 human PHD fingers revealed that ASXL PHD fingers cluster with those of BPTF, DIDO, ING1, KDM5A (JARID1A), KMT2E (MLL5), PHF2, PHF8 and PHF23. The cell context-dependent epigenetic code of ASXLs should be deciphered to develop therapeutics for human diseases.

PMID: 25835095 [PubMed - indexed for MEDLINE]

A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review.

January 21, 2016 - 7:24am

A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review.

Am J Med Genet A. 2016 Jan 20;

Authors: Merner N, Forgeot d'Arc B, Bell SC, Maussion G, Peng H, Gauthier J, Crapper L, Hamdan FF, Michaud JL, Mottron L, Rouleau GA, Ernst C

Abstract
Mutations in chromodomain helicase DNA-binding domain 8 (CHD8) have been identified in independent genotyping studies of autism spectrum disorder. To better understand the phenotype associated with CHD8 mutations, we genotyped all CHD8 exons in carefully assessed cohorts of autism (n = 142), schizophrenia (SCZ; n = 143), and intellectual disability (ID; n = 94). We identified one frameshift mutation, seven non-synonymous variants, and six synonymous variants. The frameshift mutation, p.Asn2092Lysfs*2, which creates a premature stop codon leading to the loss of 212 amino acids of the protein, was from an autism case on whom we present multiple clinical assessments and pharmacological treatments spanning more than 10 years. RNA and protein analysis support a model where the transcript generated from the mutant allele results in haploinsufficiency of CHD8. This case report supports the association of CHD8 mutations with classical autism, macrocephaly, infantile hypotonia, speech delay, lack of major ID, and psychopathology in late adolescence caused by insufficient dosage of CHD8. Review of 16 other CHD8 mutation cases suggests that clinical features and their severity vary considerably across individuals; however, these data support a CHD8 mutation syndrome, further highlighting the importance of genomic medicine to guide clinical assessment and treatment. © 2016 Wiley Periodicals, Inc.

PMID: 26789910 [PubMed - as supplied by publisher]

Meta-analysis and association of two common polymorphisms of the human oxytocin receptor gene in autism spectrum disorder.

January 21, 2016 - 7:24am

Meta-analysis and association of two common polymorphisms of the human oxytocin receptor gene in autism spectrum disorder.

Autism Res. 2016 Jan 20;

Authors: Kranz TM, Kopp M, Waltes R, Sachse M, Duketis E, Jarczok TA, Degenhardt F, Görgen K, Meyer J, Freitag CM, Chiocchetti AG

Abstract
Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnicities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymorphisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR = 1.48, CI95 = 1.06-2.08, P = 0.022) for the minor A allele of variant rs237889G>A in sample 1 (N = 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N = 542 families), this finding was confirmed (OR = 1.12; CI95 = 1.01-1.24, random effects P = 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview - revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 26788924 [PubMed - as supplied by publisher]

CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome.

January 21, 2016 - 7:24am

CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome.

Mol Genet Genomic Med. 2016 Jan;4(1):39-45

Authors: Wincent J, Luthman A, van Belzen M, van der Lans C, Albert J, Nordgren A, Anderlid BM

Abstract
Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant congenital disorder characterized by distinctive facial features, broad thumbs and halluces, growth retardation, and a variable degree of cognitive impairment. CREBBP is the major causative gene and mutations in EP300 are the cause of RTS in a minority of patients. In this study, 17 patients with a clinical diagnosis of RTS were investigated with direct sequencing, MLPA, and array-CGH in search for mutations in these two genes. Eleven patients (64.7%) had disease-causing point mutations or a deletion in CREBBP and in one patient (5.9%) a causal de novo frameshift mutation in EP300 was identified. This patient had broad thumbs, mild intellectual disability, and autism. In addition, an inherited missense mutation of uncertain clinical significance was identified in EP300 in one patient and his healthy father, and three patients had intronic nucleotide changes of uncertain clinical significance in CREBBP. Snoring and sleep apnea were common in both groups and four of the patients' mothers had preeclampsia during pregnancy. Importantly, difficulties associated with anesthesia were frequently reported and included delayed or complicated emergency in 53.3% of patients.

PMID: 26788536 [PubMed]

Formation of functional areas in the cerebral cortex is disrupted in a mouse model of autism spectrum disorder.

January 21, 2016 - 7:24am
Related Articles

Formation of functional areas in the cerebral cortex is disrupted in a mouse model of autism spectrum disorder.

Neural Dev. 2015;10:10

Authors: Fenlon LR, Liu S, Gobius I, Kurniawan ND, Murphy S, Moldrich RX, Richards LJ

Abstract
BACKGROUND: Autism spectrum disorders (ASD) are a group of poorly understood behavioural disorders, which have increased in prevalence in the past two decades. Animal models offer the opportunity to understand the biological basis of these disorders. Studies comparing different mouse strains have identified the inbred BTBR T + tf/J (BTBR) strain as a mouse model of ASD based on its anti-social and repetitive behaviours. Adult BTBR mice have complete agenesis of the corpus callosum, reduced cortical thickness and changes in early neurogenesis. However, little is known about the development or ultimate organisation of cortical areas devoted to specific sensory and motor functions in these mice that may also contribute to their behavioural phenotype.
RESULTS: In this study, we performed diffusion tensor imaging and tractography, together with histological analyses to investigate the emergence of functional areas in the cerebral cortex and their connections in BTBR mice and age-matched C57Bl/6 control mice. We found evidence that neither the anterior commissure nor the hippocampal commissure compensate for the loss of callosal connections, indicating that no interhemispheric neocortical connectivity is present in BTBR mice. We also found that both the primary visual and somatosensory cortical areas are shifted medially in BTBR mice compared to controls and that cortical thickness is differentially altered in BTBR mice between cortical areas and throughout development.
CONCLUSIONS: We demonstrate that interhemispheric connectivity and cortical area formation are altered in an age- and region-specific manner in BTBR mice, which may contribute to the behavioural deficits previously observed in this strain. Some of these developmental patterns of change are also present in human ASD patients, and elucidating the aetiology driving cortical changes in BTBR mice may therefore help to increase our understanding of this disorder.

PMID: 25879444 [PubMed - indexed for MEDLINE]

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