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A twin study of heritable and shared environmental contributions to autism.

October 21, 2014 - 7:17am
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A twin study of heritable and shared environmental contributions to autism.

J Autism Dev Disord. 2014 Aug;44(8):2013-25

Authors: Frazier TW, Thompson L, Youngstrom EA, Law P, Hardan AY, Eng C, Morris N

Abstract
The present study examined genetic and shared environment contributions to quantitatively-measured autism symptoms and categorically-defined autism spectrum disorders (ASD). Participants included 568 twins from the Interactive Autism Network. Autism symptoms were obtained using the Social Communication Questionnaire and Social Responsiveness Scale. Categorically-defined ASD was based on clinical diagnoses. DeFries-Fulker and liability threshold models examined etiologic influences. Very high heritability was observed for extreme autism symptom levels ([Formula: see text]). Extreme levels of social and repetitive behavior symptoms were strongly influenced by common genetic factors. Heritability of categorically-defined ASD diagnosis was comparatively low (.21, 95 % CI 0.15-0.28). High heritability of extreme autism symptom levels confirms previous observations of strong genetic influences on autism. Future studies will require large, carefully ascertained family pedigrees and quantitative symptom measurements.

PMID: 24604525 [PubMed - indexed for MEDLINE]

Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.

October 20, 2014 - 6:52am

Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.

Nat Genet. 2014 Oct 19;

Authors: Antonacci F, Dennis MY, Huddleston J, Sudmant PH, Steinberg KM, Rosenfeld JA, Miroballo M, Graves TA, Vives L, Malig M, Denman L, Raja A, Stuart A, Tang J, Munson B, Shaffer LG, Amemiya CT, Wilson RK, Eichler EE

Abstract
Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (∼0.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons-a ∼14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15.

PMID: 25326701 [PubMed - as supplied by publisher]

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

October 18, 2014 - 6:18am

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

Psychiatr Genet. 2014 Oct 16;

Authors: Radoeva PD, Coman IL, Salazar CA, Gentile KL, Higgins AM, Middleton FA, Antshel KM, Fremont W, Shprintzen RJ, Morrow BE, Kates WR

Abstract
Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS.

PMID: 25325218 [PubMed - as supplied by publisher]

Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.

October 18, 2014 - 6:18am

Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.

Arch Dis Child. 2014 Oct 16;

Authors: Laffargue F, Bourthoumieu S, Llanas B, Baudouin V, Lahoche A, Morin D, Bessenay L, De Parscau L, Cloarec S, Delrue MA, Taupiac E, Dizier E, Laroche C, Bahans C, Yardin C, Lacombe D, Guigonis V

Abstract
OBJECTIVE: 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation.
PATIENTS AND DESIGN: Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders.
RESULTS: The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school.
CONCLUSIONS: Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling.

PMID: 25324567 [PubMed - as supplied by publisher]

A comparative study of health locus of control in patients with schizophrenia and their first degree relatives.

October 18, 2014 - 6:18am
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A comparative study of health locus of control in patients with schizophrenia and their first degree relatives.

Asian J Psychiatr. 2014 Feb;7(1):34-7

Authors: Thakral S, Bhatia T, Gettig EA, Nimgaonkar VL, Deshpande SN

Abstract
BACKGROUND AND AIMS: An individual's behaviour may be predicted from their beliefs about their locus of control (attribution). A person's "locus" can be internal or external. The present study aimed at comparing the locus of control as measured by Multidimensional Health Locus of Control Scale (MHLC) in patients with schizophrenia and their healthy first degree relatives. We hypothesized that persons with schizophrenia have different locus of control than their first degree relatives.
METHOD: Multidimensional Health Locus of Control Scale (MHLC) was first translated and validated in Hindi by bilingual students (N = 71). Consecutive patients affected with schizophrenia (SZ) (N = 125) and their siblings/offsprings (N = 119) were recruited. Diagnostic Interview for Genetic Studies and MHLC Scale were administered after written informed consent.
RESULTS: There was moderate intra-class correlation between Hindi and English versions of MHLC Scale. Schizophrenia patients were found to have more of 'chance' locus of control (F 6.625, p = 0.011) whereas their first degree relatives have more of 'internal' locus of control (F 6.760, p = 0.010).
CONCLUSION: Patients with SZ attributed their health to external factors which has been found to be associated with poor or late recovery. These findings may provide a theoretical base for developing intervention strategies to promote behavioural changes in patients.

PMID: 24524707 [PubMed - indexed for MEDLINE]

A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chinese population.

October 18, 2014 - 6:18am
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A commonly carried genetic variant, rs9616915, in SHANK3 gene is associated with a reduced risk of autism spectrum disorder: replication in a Chinese population.

Mol Biol Rep. 2014 Mar;41(3):1591-5

Authors: Shao S, Xu S, Yang J, Zhang T, He Z, Sun Z, Song R

Abstract
Autism spectrum disorder (ASD) is one of neurodevelopmental disorders with highly heritability. Recently, abnormality at the synapse is found to be important etiology of ASD. SHANK3 gene is suggested as a strong candidate gene for the pathogenesis of ASD, because it is essential for normally synaptic structure and function. We performed a case-control study to identify association between rs9616915 of the SHANK3 gene and ASD in a Chinese population. Genomic DNA was extracted from oral swabs samples of 212 patients and 636 controls and the SNP genotypes were determined by a polymerase chain reaction-restriction fragment length polymerase assay. Significant difference in genotype distribution of rs9616915 was observed between cases and controls by Pearson's χ(2) test (χ(2) = 6.92, P = 0.031). Genetic analysis of heterozygous model, dominant model and additive model showed an association of the C allele of the rs9616915 with ASD (e.g., additive model, OR 0.582, 95% CI 0.359-0.942, P = 0.028). In conclusion, our results suggested that this commonly genetic variant in SHANK3 gene strikingly decreased the risk of ASD in China.

PMID: 24398551 [PubMed - indexed for MEDLINE]

Copy-number variation in the pathogenesis of autism spectrum disorder.

October 18, 2014 - 6:18am
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Copy-number variation in the pathogenesis of autism spectrum disorder.

Psychiatry Clin Neurosci. 2014 Feb;68(2):85-95

Authors: Shishido E, Aleksic B, Ozaki N

Abstract
Autism spectrum disorder is a neurodevelopmental disorder present in 1% of the population, characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Approximately 10% of the autism spectrum disorder population is thought to have large chromosomal rearrangements. Copy-number variations (CNV) alter the genome structure either by duplication or deletion of a chromosomal region. The association between CNV and autism susceptibility has become more apparent through the use of methods based on comparative genomic hybridization in screening CNV. The nature of the high CNV rate in the human genome is partly explained by non-allelic homologous recombination between flanking repeated sequences derived from multiple copies of transposons or mobile genetic elements. There are hotspots for CNV in the human genome, such as 16p11.2 and 22q11.2. Genes involved in CNV are supposed to have copy-number dose-dependent effects on the behavior of affected individuals. Animal models give insight into the possible interactions between core genetic loci and additional factors contributing to the phenotypes of each individual. If affected genes code for cellular signaling molecules, reducing the dosage in the intracellular signaling pathway may result in the malfunction of the nervous system. The genetic background of autism spectrum disorder is highly heterogenic and most common or rare CNV do not lead to autism spectrum disorders in the majority of cases, but may occasionally increase the risk of developing an autism spectrum disorder.

PMID: 24372918 [PubMed - indexed for MEDLINE]

MTHFR 1298A>C is a risk factor for autism spectrum disorder in the Korean population.

October 18, 2014 - 6:18am
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MTHFR 1298A>C is a risk factor for autism spectrum disorder in the Korean population.

Psychiatry Res. 2014 Jan 30;215(1):258-9

Authors: Park J, Ro M, Pyun JA, Nam M, Bang HJ, Yang JW, Choi KS, Kim SK, Chung JH, Kwack K

PMID: 24295761 [PubMed - indexed for MEDLINE]

Association between the polymorphisms of the selected genes encoding dopaminergic system with ADHD and autism.

October 18, 2014 - 6:18am
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Association between the polymorphisms of the selected genes encoding dopaminergic system with ADHD and autism.

Psychiatry Res. 2014 Jan 30;215(1):260-1

Authors: Nikolac Perkovic M, Nedic Erjavec G, Stefulj J, Muck-Seler D, Pivac N, Kocijan Hercigonja D, Hranilovic D, Curkovic M, Dodig-Curkovic K

PMID: 24210742 [PubMed - indexed for MEDLINE]

Social impairments in chromosome 22q11.2 deletion syndrome (22q11.2DS): autism spectrum disorder or a different endophenotype?

October 18, 2014 - 6:18am
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Social impairments in chromosome 22q11.2 deletion syndrome (22q11.2DS): autism spectrum disorder or a different endophenotype?

J Autism Dev Disord. 2014 Apr;44(4):739-46

Authors: Angkustsiri K, Goodlin-Jones B, Deprey L, Brahmbhatt K, Harris S, Simon TJ

Abstract
High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation measure (Autism Diagnostic Observation Schedule) and suggests that ASD is not as common as previously reported in 22q11.2DS. Differences in methodology, along with comorbid conditions such as anxiety, likely contribute to false elevations in ASD prevalence and information from multiple sources should be included in the evaluation of ASD.

PMID: 24045981 [PubMed - indexed for MEDLINE]

Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders.

October 18, 2014 - 6:18am
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Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders.

J Autism Dev Disord. 2013 Nov;43(11):2686-95

Authors: Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, Rossi F, Fasano A, Bradstreet JJ, Maione S, Antonucci N

Abstract
Autistic disorders (ADs) are heterogeneous neurodevelopmental disorders arised by the interaction of genes and environmental factors. Dysfunctions in social interaction and communication skills, repetitive and stereotypic verbal and non-verbal behaviours are common features of ADs. There are no defined mechanisms of pathogenesis, rendering curative therapy very difficult. Indeed, the treatments for autism presently available can be divided into behavioural, nutritional and medical approaches, although no defined standard approach exists. Autistic children display immune system dysregulation and show an altered immune response of peripheral blood mononuclear cells (PBMCs). In this study, we investigated the involvement of cannabinoid system in PBMCs from autistic children compared to age-matched normal healthy developing controls (age ranging 3-9 years; mean age: 6.06 ± 1.52 vs. 6.14 ± 1.39 in autistic children and healthy subjects, respectively). The mRNA level for cannabinoid receptor type 2 (CB2) was significantly increased in AD-PBMCs as compared to healthy subjects (mean ± SE of arbitrary units: 0.34 ± 0.03 vs. 0.23 ± 0.02 in autistic children and healthy subjects, respectively), whereas CB1 and fatty acid amide hydrolase mRNA levels were unchanged. mRNA levels of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D gene were slightly decreased. Protein levels of CB-2 were also significantly increased in autistic children (mean ± SE of arbitrary units: 33.5 ± 1.32 vs. 6.70 ± 1.25 in autistic children and healthy subjects, respectively). Our data indicate CB2 receptor as potential therapeutic target for the pharmacological management of the autism care.

PMID: 23585028 [PubMed - indexed for MEDLINE]

Subclinical inflammatory status in Rett syndrome.

October 17, 2014 - 2:58pm
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Subclinical inflammatory status in Rett syndrome.

Mediators Inflamm. 2014;2014:480980

Authors: Cortelazzo A, De Felice C, Guerranti R, Signorini C, Leoncini S, Pecorelli A, Zollo G, Landi C, Valacchi G, Ciccoli L, Bini L, Hayek J

Abstract
Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., "pseudo-autistic") RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P < 0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P = 0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n = 6 spots) or negative (n = 9 spots), and to a lesser extent as proteins involved in the immune system (n = 2 spots), with some proteins having overlapping functions on metabolism (n = 7 spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the "pseudo-autistic" phase of RTT, which is related to the severity carried by the MECP2 gene mutation.

PMID: 24511209 [PubMed - indexed for MEDLINE]

Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis.

October 17, 2014 - 2:58pm
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Reelin gene variants and risk of autism spectrum disorders: an integrated meta-analysis.

Am J Med Genet B Neuropsychiatr Genet. 2014 Mar;165B(2):192-200

Authors: Wang Z, Hong Y, Zou L, Zhong R, Zhu B, Shen N, Chen W, Lou J, Ke J, Zhang T, Wang W, Miao X

Abstract
Autism spectrum disorder (ASD) is a severe neurological disorder with a high degree of heritability. Reelin gene (RELN), which plays a crucial role in the migration and positioning of neurons during brain development, has been strongly posed as a candidate gene for ASD. Genetic variants in RELN have been investigated as risk factors of ASD in numerous epidemiologic studies but with inconclusive results. To clearly discern the effects of RELN variants on ASD, the authors conducted a meta-analysis integrating case-control and transmission disequilibrium test (TDT) studies published through 2001 to 2013. Odds ratios (ORs) with 95% confidence intervals were used to estimate the associations between three RELN variants (rs736707, rs362691, and GGC repeat variant) and ASD. In overall meta-analysis, the summary ORs for rs736707, rs362691, and GGC repeat variant were 1.11 [95% confidence interval (CI): 0.80-1.54], 0.69 (95% CI: 0.56-0.86), and 1.09 (95% CI: 0.97-1.23), respectively. Besides, positive result was also obtained in subgroup of broadly-defined ASD for rs362691 (OR = 0.67, 95% CI: 0.52-0.86). Our meta-analysis revealed that the RELN rs362691, rather than rs736707 or GGC repeat variant, might contribute significantly to ASD risk.

PMID: 24453138 [PubMed - indexed for MEDLINE]

Translational regulation of NeuroD1 expression by FMRP: involvement in glutamatergic neuronal differentiation of cultured rat primary neural progenitor cells.

October 17, 2014 - 2:58pm
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Translational regulation of NeuroD1 expression by FMRP: involvement in glutamatergic neuronal differentiation of cultured rat primary neural progenitor cells.

Cell Mol Neurobiol. 2014 Mar;34(2):297-305

Authors: Jeon SJ, Kim JW, Kim KC, Han SM, Go HS, Seo JE, Choi CS, Ryu JH, Shin CY, Song MR

Abstract
Fragile X mental retardation protein (FMRP) is encoded by Fmr1 gene in which mutation is known to cause fragile X syndrome characterized by mental impairment and other psychiatric symptoms similar to autism spectrum disorders. FMRP plays important roles in cellular mRNA biology such as transport, stability, and translation as an RNA-binding protein. In the present study, we identified potential role of FMRP in the neural differentiation, using cortical neural progenitor cells from Sprague-Dawley rat. We newly found NeuroD1, an essential regulator of glutamatergic neuronal differentiation, as a new mRNA target interacting with FMRP in co-immunoprecipitation experiments. We also identified FMRP as a regulator of neuronal differentiation by modulating NeuroD1 expression. Down-regulation of FMRP by siRNA also increased NeuroD1 expression along with increased pre- and post-synaptic development of glutamatergic neuron, as evidenced by Western blot and immunocytochemistry. On the contrary, cells harboring FMRP over-expression construct showed decreased NeuroD1 expression. Treatment of cultured neural precursor cells with a histone deacetylase inhibitor, valproic acid known as an inducer of hyper-glutamatergic neuronal differentiation, down-regulated the expression of FMRP, and induced NeuroD1 expression. Our study suggests that modulation of FMRP expression regulates neuronal differentiation by interaction with its binding target mRNA, and provides an example of the gene and environmental interaction regulating glutamatergic neuronal differentiation.

PMID: 24338128 [PubMed - indexed for MEDLINE]

Brief report: do the nature of communication impairments in autism spectrum disorders relate to the broader autism phenotype in parents?

October 17, 2014 - 2:58pm
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Brief report: do the nature of communication impairments in autism spectrum disorders relate to the broader autism phenotype in parents?

J Autism Dev Disord. 2013 Dec;43(12):2984-9

Authors: Taylor LJ, Maybery MT, Wray J, Ravine D, Hunt A, Whitehouse AJ

Abstract
Extensive empirical evidence indicates that the lesser variant of Autism Spectrum Disorders (ASD) involves a communication impairment that is similar to, but milder than, the deficit in clinical ASD. This research explored the relationship between the broader autism phenotype (BAP) among parents, an index of genetic liability for ASD, and proband communication difficulties. ASD probands with at least one BAP parent (identified using the Autism Spectrum Quotient) had greater structural and pragmatic language difficulties (assessed using the Children's Communication Checklist-2) than ASD probands with no BAP parent. This finding provides support for the position that genetic liability for ASD is associated with increased communication difficulties across structural and pragmatic domains.

PMID: 23619954 [PubMed - indexed for MEDLINE]

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans.

October 16, 2014 - 8:14am

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans.

Genetics. 2014 Oct;198(2):723-33

Authors: Brooks SS, Wall AL, Golzio C, Reid DW, Kondyles A, Willer JR, Botti C, Nicchitta CV, Katsanis N, Davis EE

Abstract
Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant. Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function.

PMID: 25316788 [PubMed - in process]

Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study.

October 16, 2014 - 8:14am

Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study.

BMJ Open. 2014;4(10):e005974

Authors: Antoniou EE, Fowler T, Reed K, Southwood TR, McCleery JP, Zeegers MP

Abstract
OBJECTIVE: To estimate the heritability of child behaviour problems and investigate the association between maternal pre-pregnancy overweight and child behaviour problems in a genetically sensitive design.
DESIGN: Observational cross-sectional study.
SETTING: The Twins and Multiple Births Association Heritability Study (TAMBAHS) is an online UK-wide volunteer-based study investigating the development of twins from birth until 5 years of age.
PARTICIPANTS: A total of 443 (16% of the initial registered members) mothers answered questions on pre-pregnancy weight and their twins' internalising and externalising problems using the Child Behavior Checklist and correcting for important covariates including gestational age, twins' birth weight, age and sex, mother's educational level and smoking (before, during and after pregnancy).
PRIMARY OUTCOMES: The heritability of behaviour problems and their association with maternal pre-pregnancy weight.
RESULTS: The genetic analysis suggested that genetic and common environmental factors account for most of the variation in externalising disorders (an ACE model was the most parsimonious with genetic factors (A) explaining 46% (95% CI 33% to 60%) of the variance, common environment (C) explaining 42% (95% CI 27% to 54%) and non-shared environmental factors (E) explaining 13% (95% CI 10% to 16%) of the variance. For internalising problems, a CE model was the most parsimonious model with the common environment explaining 51% (95% CI 44% to 58%) of the variance and non-shared environment explaining 49% (95% CI 42% to 56%) of the variance. Moreover, the regression analysis results suggested that children of overweight mothers showed a trend (OR=1.10, 95% CI 0.58% to 2.06) towards being more aggressive and exhibit externalising behaviours compared to children of normal weight mothers.
CONCLUSIONS: Maternal pre-pregnancy weight may play a role in children's aggressive behaviour.

PMID: 25314961 [PubMed - in process]

[Diagnostics of the genetic causes of autism spectrum disorders - a clinical geneticist's view].

October 16, 2014 - 8:14am

[Diagnostics of the genetic causes of autism spectrum disorders - a clinical geneticist's view].

Psychiatr Pol. 2014 Jul-Aug;48(4):677-88

Authors: Szczaluba K

Abstract
Explanation of the genetic basis of autism spectrum disorders has, for many decades, been a part of interest of researchers and clinicians. In recent years, thanks to modern molecular and cytogenetic techniques, a significant progress has been achieved in the diagnosis of genetic causes of autism. This applies particularly, but not exclusively, to those cases of autism that are accompanied by other clinical signs (i. e. complex phenotypes). The important clinical markers belong to different categories, and include congenital defects/anomalies, dysmorphism and macro-/microcephaly, to name the few. Thus, the choice of the diagnostic strategy depends on the clinical and pedigree information and, under Polish circumstances, the availability of specific diagnostic techniques and the amount of reimbursement under the National Health Service. Overall, the identification of the genetic causes of autism spectrum disorders is possible in about 10-30% of patients. In this paper the practical aspects of the use of different diagnostic techniques are briefly described. Some clinical examples and current recommendations for the diagnosis of patients with autism spectrum disorders are also presented. The point of view of a specialist in clinical genetics, increasingly involved, as part of the multidisciplinary care team, in the diagnostics of an autistic child has been demonstrated.

PMID: 25314796 [PubMed - in process]

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

October 15, 2014 - 7:30am

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

Mol Psychiatry. 2014 Oct 14;

Authors: Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D, Bill BR, Berg JM, Gao F, Coppola G, Abrahams BS, Geschwind DH

Abstract
Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.Molecular Psychiatry advance online publication, 14 October 2014; doi:10.1038/mp.2014.124.

PMID: 25311365 [PubMed - as supplied by publisher]

Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity.

October 14, 2014 - 7:12am

Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity.

Mamm Genome. 2014 Oct 12;

Authors: Keeney JG, O'Bleness MS, Anderson N, Davis JM, Arevalo N, Busquet N, Chick W, Rozman J, Hölter SM, Garrett L, Horsch M, Beckers J, Wurst W, Klingenspor M, Restrepo D, German Mouse Clinic Consortium, Sikela JM, de Angelis MH

Abstract
Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ (2) = 19.1, df = 2, p = 7.0 × 10(-5)). Further extensive phenotypic analyses suggest hyperactivity (p < 0.05) of DUF1220 mice and changes in gene expression levels of brain associated with distinct neurological functions and disease. Other changes that met statistical significance include an increase in plasma glucose concentration (as measured by area under the curve, AUC 0-30 and AUC 30-120) in male mutants, fasting glucose levels, reduce sodium levels in male mutants, increased levels of the liver functional indicator ALAT/GPT in males, levels of alkaline phosphatase (also an indicator of liver function), mean R and SR amplitude by electrocardiography, elevated IgG3 levels, a reduced ratio of CD4:CD8 cells, and a reduced frequency of T cells; though it should be noted that many of these differences are quite small and require further examination. The linking of DUF1220 loss to a hyperactive phenotype is consistent with separate findings in which DUF1220 over expression results in a down-regulation of mitochondrial function, and potentially suggests a role in developmental metabolism. Finally, the substantially reduced fecundity we observe associated with KO mice argues that the ancestral DUF1220 domain provides an important biological functionthat is critical to survivability and reproductive success.

PMID: 25308000 [PubMed - as supplied by publisher]

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