pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 2 days 16 hours ago

Rare structural genetic variation in human prion diseases.

March 2, 2016 - 6:43am
Related Articles

Rare structural genetic variation in human prion diseases.

Neurobiol Aging. 2015 May;36(5):2004.e1-8

Authors: Lukic A, Uphill J, Brown CA, Beck J, Poulter M, Campbell T, Adamson G, Hummerich H, Whitfield J, Ponto C, Zerr I, Lloyd SE, Collinge J, Mead S

Abstract
Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

PMID: 25726360 [PubMed - indexed for MEDLINE]

A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.

March 2, 2016 - 6:43am
Related Articles

A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.

J Hum Genet. 2015 May;60(5):277-9

Authors: Fukai R, Hiraki Y, Yofune H, Tsurusaki Y, Nakashima M, Saitsu H, Tanaka F, Miyake N, Matsumoto N

Abstract
Autism spectrum disorder (ASD) is a clinically heterogeneous psychiatric disorder with various genetic backgrounds. Here, we report a novel mutation in the pogo transposable element-derived protein with zinc finger domain gene (POGZ) identified by trio-based whole exome sequencing. To date, a total of seven de novo POGZ mutations in ASD have been reported. POGZ contains a total of five functional domains, and this study reports the first de novo missense mutation in the centromere protein B-like DNA-binding domain. POGZ is highly expressed in the human fetal brain and is involved in mitosis and the regulation of neuronal proliferation. Therefore its loss-of-function or pathogenic missense mutations are likely to be causative of ASD.

PMID: 25694107 [PubMed - indexed for MEDLINE]

Rare copy number variants are common in young children with autism spectrum disorder.

March 2, 2016 - 6:43am
Related Articles

Rare copy number variants are common in young children with autism spectrum disorder.

Acta Paediatr. 2015 Jun;104(6):610-8

Authors: Eriksson MA, Liedén A, Westerlund J, Bremer A, Wincent J, Sahlin E, Gillberg C, Fernell E, Anderlid BM

Abstract
AIM: Several studies have suggested that rare copy number variants (CNVs) are an important genetic contributor to autism spectrum disorders. The aims of the study were to use chromosomal microarray to investigate the presence of rare copy number variants in a population-based cohort of well-characterised young children with autism spectrum disorders and to relate the genetic results to neurodevelopmental profiles and medical conditions.
METHODS: We performed chromosomal microarray on samples from 162 children who had been referred to the Stockholm Autism Centre for Young Children in Sweden after being diagnosed with autism spectrum disorder between 20 and 54 months of age.
RESULTS: Pathogenic aberrations were detected in 8.6% of the children and variants of uncertain significance were present in another 8.6%. CNVs were more frequent in children with congenital malformations or dysmorphic features as well as in the subgroup with intellectual disability.
CONCLUSION: Our results support the use of chromosomal microarray methods for the first tier genetic analysis of autism spectrum disorder. However, it is likely in the near future that chromosomal microarray methods will probably be replaced by whole-exome and whole-genome sequencing technologies in clinical genetic testing.

PMID: 25661985 [PubMed - indexed for MEDLINE]

Activity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer.

March 2, 2016 - 6:43am
Related Articles

Activity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer.

J Alzheimers Dis. 2015;45(1):57-73

Authors: Gozes I, Yeheskel A, Pasmanik-Chor M

Abstract
The recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer's disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations, are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics.

PMID: 25428252 [PubMed - indexed for MEDLINE]

Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1).

March 1, 2016 - 6:37am

Illness Severity, Social and Cognitive Ability, and EEG Analysis of Ten Patients with Rett Syndrome Treated with Mecasermin (Recombinant Human IGF-1).

Autism Res Treat. 2016;2016:5073078

Authors: Pini G, Congiu L, Benincasa A, DiMarco P, Bigoni S, Dyer AH, Mortimer N, Della-Chiesa A, O'Leary S, McNamara R, Mitchell KJ, Gill M, Tropea D

Abstract
Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p = 0.0106) and RSS (p = 0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum.

PMID: 26925263 [PubMed - as supplied by publisher]

[One autism, several autisms. Phenotypical variability in autism spectrum disorders].

March 1, 2016 - 6:37am

[One autism, several autisms. Phenotypical variability in autism spectrum disorders].

Rev Neurol. 2016 Feb 21;62(s01):S9-S14

Authors: Hervas A

Abstract
INTRODUCTION: Autism spectrum disorders (ASD) are a heterogeneous group of disorders that begin in the early months of life and follow a chronic progression. They have a biological origin, with complex aetiological factors that involve different genetic, epigenetic and environmental mechanisms that interact with one another.
AIM: To review the main factors that vary the presentation of autism taking into account the most recent scientific evidence.
DEVELOPMENT: Aspects related with the development of symptoms, gender, comorbidity, age and aetiology determine the variability in the clinical presentation of ASD.
CONCLUSIONS: Autism is highly heterogeneous and is phenotypically related, at least in part, with a wide range of causations, which researchers have begun to unravel but which are still largely unknown. Aetiological research, especially in the area of genetics, will make it possible to identify different homogeneous subgroups with their corresponding phenotypes, while also opening up the way to possible therapeutic alternatives in the future.

PMID: 26922965 [PubMed - as supplied by publisher]

Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders.

February 26, 2016 - 8:58am
Related Articles

Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders.

JAMA Psychiatry. 2016 Feb 24;

Authors: Nordsletten AE, Larsson H, Crowley JJ, Almqvist C, Lichtenstein P, Mataix-Cols D

Abstract
Importance: Psychiatric disorders are heritable, polygenic traits, which often share risk alleles and for which nonrandom mating has been suggested. However, despite the potential etiological implications, the scale of nonrandom mating within and across major psychiatric conditions remains unclear.
Objective: To quantify the nature and extent of nonrandom mating within and across a broad range of psychiatric conditions at the population level.
Design, Setting, and Participants: Population-based cohort using Swedish population registers. Participants were all Swedish residents with a psychiatric diagnosis of interest (attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, bipolar disorder, major depression, generalized anxiety disorder, agoraphobia, social phobia, obsessive-compulsive disorder, anorexia, or substance abuse), along with their mates. Individuals with select nonpsychiatric disorders (Crohn's disease, type 1 and type 2 diabetes mellitus, multiple sclerosis, or rheumatoid arthritis) were included for comparison. General population samples were also derived and matched 1:5 with each case proband. Inpatient and outpatient diagnostic data were derived from the Swedish National Patient Register (1973-2009), with analyses conducted between June 2014 and May 2015.
Main Outcomes and Measures: Correlation in the diagnostic status of mates both within and across disorders. Conditional logistic regression was used to quantify the odds of each diagnosis in the mates of cases relative to matched population controls.
Results: Across cohorts, data corresponded to 707 263 unique case individuals, with women constituting 45.7% of the full population. Positive correlations in diagnostic status were evident between mates. Within-disorder correlations were marginally higher (range, 0.11-0.48) than cross-disorder correlations (range, 0.01-0.42). Relative to matched populations, the odds of psychiatric case probands having an affected mate were significantly elevated. Differences in the magnitude of observed relationships were apparent by disorder (odds ratio range, 0.8-11.4). The number of comorbidities in a case proband was associated with the proportion of affected mates. These relationships were not apparent or weaker in magnitude among nonpsychiatric conditions (correlation range, -0.03 to 0.17).
Conclusions and Relevance: Nonrandom mating is evident in psychiatric populations both within specific disorders and across the spectrum of psychiatric conditions. This phenomenon may hold important implications for how we understand the familial transmission of these disorders and for psychiatric genetic research.

PMID: 26913486 [PubMed - as supplied by publisher]

Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome.

February 26, 2016 - 8:58am
Related Articles

Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome.

J Neurodev Disord. 2016;8:5

Authors: Wang AT, Lim T, Jamison J, Bush L, Soorya LV, Tavassoli T, Siper PM, Buxbaum JD, Kolevzon A

Abstract
BACKGROUND: Phelan-McDermid syndrome (PMS), a neurodevelopmental disorder caused by deletion or mutation in the SHANK3 gene, is one of the more common single-locus causes of autism spectrum disorder (ASD). PMS is characterized by global developmental delay, hypotonia, delayed or absent speech, increased risk of seizures, and minor dysmorphic features. Impairments in language and communication are one of the most consistent characteristics of PMS. Although there is considerable overlap in the social communicative deficits associated with PMS and ASD, there is a dearth of data on underlying abnormalities at the level of neural systems in PMS. No controlled neuroimaging studies of PMS have been reported to date. The goal of this study was to examine the neural circuitry supporting the perception of auditory communicative signals in children with PMS as compared to idiopathic ASD (iASD).
METHODS: Eleven children with PMS and nine comparison children with iASD were scanned using functional magnetic resonance imaging (fMRI) under light sedation. The fMRI paradigm was a previously validated passive auditory task, which presented communicative (e.g., speech, sounds of agreement, disgust) and non-communicative vocalizations (e.g., sneezing, coughing, yawning).
RESULTS: Previous research has shown that the superior temporal gyrus (STG) responds selectively to communicative vocal signals in typically developing children and adults. Here, selective activity for communicative relative to non-communicative vocalizations was detected in the right STG in the PMS group, but not in the iASD group. The PMS group also showed preferential activity for communicative vocalizations in a range of other brain regions associated with social cognition, such as the medial prefrontal cortex (MPFC), insula, and inferior frontal gyrus. Interestingly, better orienting toward social sounds was positively correlated with selective activity in the STG and other "social brain" regions, including the MPFC, in the PMS group. Finally, selective MPFC activity for communicative sounds was associated with receptive language level in the PMS group and expressive language in the iASD group.
CONCLUSIONS: Despite shared behavioral features, children with PMS differed from children with iASD in their neural response to communicative vocal sounds and showed relative strengths in this area. Furthermore, the relationship between clinical characteristics and neural selectivity also differed between the two groups, suggesting that shared ASD features may partially reflect different neurofunctional abnormalities due to differing etiologies.

PMID: 26909118 [PubMed]

Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine.

February 26, 2016 - 8:58am
Related Articles

Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine.

Neuropharmacology. 2016 Feb 20;

Authors: Golub MS, Hogrefe CE, Bulleri AM

Abstract
BACKGROUND: Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children.
METHODS: Male rhesus monkeys 1-3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n=16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA).
RESULTS: Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitations and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors.
CONCLUSIONS: Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect.

PMID: 26905291 [PubMed - as supplied by publisher]

Link Between Increased Prevalence of Autism Spectrum Disorder Syndromes and Oxidative Stress, DNA Methylation, and Imprinting: The Impact of the Environment.

February 26, 2016 - 8:58am
Related Articles

Link Between Increased Prevalence of Autism Spectrum Disorder Syndromes and Oxidative Stress, DNA Methylation, and Imprinting: The Impact of the Environment.

JAMA Pediatr. 2015 Nov;169(11):1066-7

Authors: Menezo YJ, Elder K, Dale B

PMID: 26414354 [PubMed - indexed for MEDLINE]

Proteogenomic Analysis Identifies a Novel Human SHANK3 Isoform.

February 26, 2016 - 8:58am
Related Articles

Proteogenomic Analysis Identifies a Novel Human SHANK3 Isoform.

Int J Mol Sci. 2015;16(5):11522-30

Authors: Benthani F, Tran PN, Currey N, Ng I, Giry-Laterriere M, Carey L, Kohonen-Corish MR, Pangon L

Abstract
Mutations of the SHANK3 gene have been associated with autism spectrum disorder. Individuals harboring different SHANK3 mutations display considerable heterogeneity in their cognitive impairment, likely due to the high SHANK3 transcriptional diversity. In this study, we report a novel interaction between the Mutated in colorectal cancer (MCC) protein and a newly identified SHANK3 protein isoform in human colon cancer cells and mouse brain tissue. Hence, our proteogenomic analysis identifies a new human long isoform of the key synaptic protein SHANK3 that was not predicted by the human reference genome. Taken together, our findings describe a potential new role for MCC in neurons, a new human SHANK3 long isoform and, importantly, highlight the use of proteomic data towards the re-annotation of GC-rich genomic regions.

PMID: 25997006 [PubMed - indexed for MEDLINE]

Effects of post-weaning diet on metabolic parameters and DNA methylation status of the cryptic promoter in the A(vy) allele of viable yellow mice.

February 26, 2016 - 8:58am
Related Articles

Effects of post-weaning diet on metabolic parameters and DNA methylation status of the cryptic promoter in the A(vy) allele of viable yellow mice.

J Nutr Biochem. 2015 Jun;26(6):667-74

Authors: Warzak DA, Johnson SA, Ellersieck MR, Roberts RM, Zhang X, Ho SM, Rosenfeld CS

Abstract
Mice carrying the A(vy) allele are epigenetic mosaics. If the majority of cells have an active (demethylated) intracisternal A particle (IAP), mice have a yellow coat color and develop adult-onset obesity and diabetes, while mice whose mosaicism predominantly reflects an inactive (methylated) IAP are pseudoagouti (brown) and less prone to metabolic disease. Brown and yellow coat color A(vy)/a post-weaning mice were placed on one of three diets [AIN, and two lower-calorie diets National Institutes of Health (NIH) and methyl-supplemented, NIHMe] to determine whether coat color, weight gain, blood glucose and methylation of hepatic IAP became altered. None of the diets altered A(vy)/a mice coat color. NIHMe did not protect against increasing obesity or the usual onset of hyperglycemia in males. Nor did it promote increased methylation of A(vy) IAP in liver tissue. By contrast, AIN, despite its higher content of fat and carbohydrate and ability to promote greater weight gains than the NIH and NIHMe diets, protected males better against hyperglycemia than either the NIH or NIHMe diets. This diet led to a significantly reduced (~50%; P = .003) average methylation state of all CpG sites within the hepatic IAP for the pseudoagouti mice. On AIN, but not on the other diets, extent of hepatic IAP methylation was negatively correlated (R = 0.97, P ≤ .001) with body weight of pseudoagouti mice. The findings indicate that post-weaning diet might influence interpretation of studies with A(vy)/a mice because IAP methylation patterns may be malleable in certain organs and influenced by post-weaning diet.

PMID: 25818200 [PubMed - indexed for MEDLINE]

Mother-Child Interaction as a Window to a Unique Social Phenotype in 22q11.2 Deletion Syndrome and in Williams Syndrome.

February 26, 2016 - 8:58am
Related Articles

Mother-Child Interaction as a Window to a Unique Social Phenotype in 22q11.2 Deletion Syndrome and in Williams Syndrome.

J Autism Dev Disord. 2015 Aug;45(8):2567-77

Authors: Weisman O, Feldman R, Burg-Malki M, Keren M, Geva R, Diesendruck G, Gothelf D

Abstract
Mother-child interactions in 22q11.2 Deletion syndrome (22q11.2DS) and Williams syndrome (WS) were coded for maternal sensitivity/intrusiveness, child's expression of affect, levels of engagement, and dyadic reciprocity. WS children were found to express more positive emotions towards their mothers compared to 22q11.2DS children and those with developmental delay in a conflict interaction. During the same interaction, dyads of 22q11.2DS children were characterized by higher levels of maternal intrusiveness, lower levels of child's engagement and reduced reciprocity compared to dyads of typically developing children. Finally, 22q11.2DS children with the COMT Met allele showed less adaptive behaviors than children with the Val allele. Dyadic behaviors partially coincided with the distinct social phenotypes in these syndromes and are potential behavioral markers of psychopathological trajectory.

PMID: 25791124 [PubMed - indexed for MEDLINE]

Current Update on Synopsis of miRNA Dysregulation in Neurological Disorders.

February 26, 2016 - 8:58am
Related Articles

Current Update on Synopsis of miRNA Dysregulation in Neurological Disorders.

CNS Neurol Disord Drug Targets. 2015;14(4):492-501

Authors: Kamal MA, Mushtaq G, Greig NH

Abstract
Aberrant expression of microRNAs (miRNAs) has been implicated in various neurological disorders (NDs) of the central nervous system such as Alzheimer disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia and autism. If dysregulated miRNAs are identified in patients suffering from NDs, this may serve as a biomarker for the earlier diagnosis and monitoring of disease progression. Identifying the role of miRNAs in normal cellular processes and understanding how dysregulated miRNA expression is responsible for their neurological effects is also critical in the development of new therapeutic strategies for NDs. miRNAs hold great promise from a therapeutic point of view especially if it can be proved that a single miRNA has the ability to influence several target genes, making it possible for the researchers to potentially modify a whole disease phenotype by modulating a single miRNA molecule. Hence, better understanding of the mechanisms by which miRNA play a role in the pathogenesis of NDs may provide novel targets to scientists and researchers for innovative therapies.

PMID: 25714967 [PubMed - indexed for MEDLINE]

Complex genomic variants contribute toward the genetic architecture of autism spectrum disorder.

February 24, 2016 - 8:49am
Related Articles

Complex genomic variants contribute toward the genetic architecture of autism spectrum disorder.

Psychiatr Genet. 2016 Apr;26(2):95-96

Authors: Chen CH, Liao HM, Chen HI, Fang JS, Chen YJ, Lee KF, Gau SS

PMID: 26901793 [PubMed - as supplied by publisher]

Complex intrachromosomal rearrangement in 1q leading to 1q32.2 microdeletion: a potential role of SRGAP2 in the gyrification of cerebral cortex.

February 24, 2016 - 8:49am
Related Articles

Complex intrachromosomal rearrangement in 1q leading to 1q32.2 microdeletion: a potential role of SRGAP2 in the gyrification of cerebral cortex.

Mol Cytogenet. 2016;9:19

Authors: Rincic M, Rados M, Krsnik Z, Gotovac K, Borovecki F, Liehr T, Brecevic L

Abstract
BACKGROUND: Van der Woude syndrome (MIM: 119300, VWS) is a dominantly inherited and the most common orofacial clefting syndrome; it accounts for ~2 % of all cleft lip and palate cases. Intellectual disability (ID) is characterized by significant limitations, both in intellectual functioning (cognitive deficit) and in adaptive behavior as expressed in conceptual, social and practical adaptive skills. Karyotyping has been the first standard test for the detection of genetic imbalance in patients with ID for more than 35 years. Advances in genetic diagnosis have laid chromosomal microarrays (CMA) as a new standard and first first-line test for diagnosis of patients with ID, as well as other conditions, such as autism spectrum disorders or multiple congenital anomalies.
CASE PRESENTATION: The present case was initially studied due to unexplained cognitive deficit. Physical examination at the age of 18 years revealed cleft palate, lower lip pits and hypodontia, accompanied with other dysmorphic features and absence of speech. Brain MRI uncovered significantly reduced overall volume of gray matter and cortical gyrification. Banding cytogenetics revealed an indistinct intrachromosomal rearrangement in the long arm of one chromosome 1, and subsequent microarray analyses identified a 5.56 Mb deletion in 1q32.1-1q32.3, encompassing 52 genes; included were the entire IRF6 gene (whose mutations/deletions underlay VWS) and SRGAP2, a gene with an important role in neuronal migration during development of cerebral cortex. Besides, a duplication in 3q26.32 (1.9 Mb in size) comprising TBL1XR1 gene was identified. Multicolor banding for chromosome 1 and molecular cytogenetics applying a battery of locus-specific probes covering 1q32.1 to 1q44 characterized a four breakpoint-insertional-rearrangement-event, resulting in 1q32.1-1q32.3 deletion.
CONCLUSIONS: Considering that the human-specific three-fold segmental duplication of SRGAP2 gene evolutionary corresponds to the beginning of neocortical expansion, we hypothesize that aberrations in SRGAP2 are strong candidates underlying specific brain abnormalities, namely reduced volume of grey matter and reduced gyrification.

PMID: 26900403 [PubMed]

Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders.

February 24, 2016 - 8:49am
Related Articles

Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders.

Schizophr Res. 2015 Jul;165(2-3):201-11

Authors: Folsom TD, Thuras PD, Fatemi SH

Abstract
Fragile X mental retardation protein (FMRP) is an RNA binding protein with 842 target mRNAs in mammalian brain. Silencing of the fragile X mental retardation 1 (FMR1) gene leads to loss of expression of FMRP and upregulated metabotropic glutamate receptor 5 (mGluR5) signaling resulting in the multiple physical and cognitive deficits associated with fragile X syndrome (FXS). Reduced FMRP expression has been identified in subjects with autism, schizophrenia, bipolar disorder, and major depression who do not carry the mutation for FMR1. Our laboratory has recently demonstrated altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with autism: homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP). In the current study we investigated the expression of the same four proteins in lateral cerebella of subjects with schizophrenia, bipolar disorder, and major depression and in frontal cortex of subjects with schizophrenia and bipolar disorder. In frontal cortex we observed: 1) reduced expression of 120 kDa form of APP in subjects with schizophrenia and bipolar disorder; 2) reduced expression of 61 kDa and 33k Da forms of STEP in subjects with schizophrenia; 3) reduced expression of 88 kDa form of APP in subjects with bipolar disorder; and 3) trends for reduced expression of 88 kDa form of APP and homer 1 in subjects with schizophrenia and bipolar disorder, respectively. In lateral cerebella there was no group difference, however we observed increased expression of RAC1 in subjects with bipolar disorder, and trends for increased RAC1 in subjects with schizophrenia and major depression. Our results provide further evidence that proteins involved in the FMRP-mGluR5 signaling pathway are altered in schizophrenia and mood disorders.

PMID: 25956630 [PubMed - indexed for MEDLINE]

MeCP2 plays an analgesic role in pain transmission through regulating CREB / miR-132 pathway.

February 24, 2016 - 8:49am
Related Articles

MeCP2 plays an analgesic role in pain transmission through regulating CREB / miR-132 pathway.

Mol Pain. 2015;11:19

Authors: Zhang R, Huang M, Cao Z, Qi J, Qiu Z, Chiang LY

Abstract
BACKGROUND: The Methyl CpG binding protein 2 gene (MeCP2 gene) encodes a critical transcriptional repressor and is widely expressed in mammalian neurons. MeCP2 plays a critical role in neuronal differentiation, neural development, and synaptic plasticity. Mutations and duplications of the human MECP2 gene lead to severe neurodevelopmental disorders, such as Rett syndrome and autism. In this study we investigate the role of MeCP2 in the spinal cord and found that MeCP2 plays an important role as an analgesic mediator in pain circuitry.
FINDINGS: Experiments using MeCP2 transgenic mice showed that overexpression of MeCP2 weakens both acute mechanical pain and thermal pain, suggesting an analgesic role of MeCP2 in acute pain transduction. We found that through p-CREB/miR-132 signaling cascade is involved in MeCP2-mediated pain transduction. We also examined the role of MeCP2 in chronic pain formation using spared nerve injury (SNI) model. Strikingly, we found that development of neuropathic pain attenuates in MeCP2 transgenic mice comparing to wild type (WT) mice.
CONCLUSIONS: Our study shows that MeCP2 plays an analgesic role in both acute pain transduction and chronic pain formation through regulating CREB-miR-132 pathway. This work provides a potential therapeutic target for neural pathologic pain, and also sheds new lights on the abnormal sensory mechanisms associated with autism spectrum orders.

PMID: 25885346 [PubMed - indexed for MEDLINE]

Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.

February 24, 2016 - 8:49am
Related Articles

Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.

J Med Genet. 2015 Feb;52(2):128-34

Authors: Spinelli L, Black FM, Berg JN, Eickholt BJ, Leslie NR

Abstract
BACKGROUND: Germline mutations in the phosphatase PTEN are associated with diverse human pathologies, including tumour susceptibility, developmental abnormalities and autism, but any genotype-phenotype relationships are poorly understood.
METHODS: We have studied the functional consequences of seven PTEN mutations identified in patients diagnosed with autism and macrocephaly and five mutations from severe tumour bearing sufferers of PTEN hamartoma tumour syndrome (PHTS).
RESULTS: All seven autism-associated PTEN mutants investigated retained the ability to suppress cellular AKT signalling, although five were highly unstable. Observed effects on AKT also correlated with the ability to suppress soma size and the length and density of dendritic spines in primary neurons. Conversely, all five PTEN mutations from severe cases of PHTS appeared to directly and strongly disrupt the ability to inhibit AKT signalling.
CONCLUSIONS: Our work implies that alleles causing incomplete loss of PTEN function are more commonly linked to autism than to severe PHTS cases.

PMID: 25527629 [PubMed - indexed for MEDLINE]

Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila.

February 21, 2016 - 8:27am

Neurofibromin Loss of Function Drives Excessive Grooming in Drosophila.

G3 (Bethesda). 2016 Feb 19;

Authors: King LB, Koch M, Murphy K, Velazquez Y, Ja WW, Tomchik SM

Abstract
Neurofibromatosis I is a common genetic disorder that results in tumor formation and predisposes individuals to a range of cognitive/behavioral symptoms, including deficits in attention, visuospatial skills, learning, language development, sleep, and autism spectrum disorder-like traits. The nf1-encoded neurofibromin protein (Nf1) exhibits high conservation, from the common fruit fly, Drosophila melanogaster, to humans. Drosophila provide a powerful platform to investigate the signaling cascades upstream and downstream of Nf1, and the fly model exhibits similar behavioral phenotypes to mammalian models. In order to understand how loss of Nf1 affects motor behavior in flies, we combined traditional activity monitoring with video analysis of grooming behavior. In nf1 mutants, spontaneous grooming was increased up to 7x. This increase in activity was distinct from previously-described dopamine-dependent hyperactivity, as dopamine transporter mutants exhibited slightly decreased grooming. Finally, we found that relative grooming frequencies can be compared in standard activity monitors that measure infrared beam breaks, enabling the use of activity monitors as an automated method to screen for grooming phenotypes. Overall, these data suggest that loss of nf1 produces excessive activity that is manifested as increased grooming, providing a platform to dissect the molecular genetics of neurofibromin signaling across neuronal circuits.

PMID: 26896440 [PubMed - as supplied by publisher]

Pages