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Social memory, amnesia, and autism: brain oxytocin secretion is regulated by NAD+ metabolites and single nucleotide polymorphisms of CD38.

April 16, 2014 - 8:49am
Related Articles

Social memory, amnesia, and autism: brain oxytocin secretion is regulated by NAD+ metabolites and single nucleotide polymorphisms of CD38.

Neurochem Int. 2012 Nov;61(6):828-38

Authors: Higashida H, Yokoyama S, Huang JJ, Liu L, Ma WJ, Akther S, Higashida C, Kikuchi M, Minabe Y, Munesue T

Abstract
Previously, we demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin (OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in Cd38 knockout mice. The autism spectrum disorders (ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. However, the etiology of ASDs remains largely unknown. Therefore, the theoretical basis for pharmacological treatments has not been established. Hence, there is a rationale for investigating single nucleotide polymorphisms (SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 (C>A) was associated with high-functioning autism (HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561 (4693C>T), leads to the substitution of an arginine (R) at codon 140 by tryptophan (W; R140W) in CD38. This mutation was found in four probands of ASD and in family members of three pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. The OXT levels were unchanged in healthy subjects with or without this mutation. One proband with the R140W allele receiving intranasal OXT for approximately 3years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. Five other ASD subjects with mental deficits received nasal OXT for various periods; three subjects showed improved symptoms, while two showed little or no effect. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials.

PMID: 22366648 [PubMed - indexed for MEDLINE]

Focusing on Cause or Cure?: Priorities and Stakeholder Presence in Childhood Psychiatry Research.

April 15, 2014 - 8:26am

Focusing on Cause or Cure?: Priorities and Stakeholder Presence in Childhood Psychiatry Research.

AJOB Prim Res. 2014 Jan 1;5(1):44-55

Authors: Milner LC, Cho MK

Abstract
BACKGROUND: Biomedical research is influenced by many factors, including the involvement of stakeholder groups invested in research outcomes. Stakeholder involvement in research efforts raise questions of justice as their specific interests and motivations play a role in directing research resources that ultimately produce knowledge shaping how different conditions (and affected individuals) are understood and treated by society. This issue is highly relevant to child psychiatry research where diagnostic criteria and treatment strategies are often controversial. Biological similarities and stakeholder differences between attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) provide an opportunity to explore this issue by comparing research foci and stakeholder involvement in these conditions.
METHODS: A subset of ADHD and ASD research articles published between 1970-2010 were randomly selected from the PubMed database and coded for research focus, funding source(s), and author-reported conflicts of interest (COIs). Chi-square analyses were performed to identify differences between and within ADHD and ASD research across time.
RESULTS: The proportion of ADHD research dedicated to basic, description, and treatment research was roughly similar and remained stable over time, while ASD research showed a significant increase in basic research over the past decade. Government was the primary research funder for both conditions, but for-profit funders were a notable presence in ADHD research, while joint-funding efforts between non-profit and government funders were a notable presence in ASD research. Lastly, COIs were noted more frequently in ADHD than in ASD research.
CONCLUSIONS: Our study shows significant differences in research foci and funding sources between the conditions, and identifies the specific involvement of for-profit and non-profit groups in ADHD and ASD, respectively. Our findings highlight the relationship between stakeholders outside the research community and research trajectories and suggest that examinations of these relationships must be included in broader considerations of biomedical research ethics.

PMID: 24729931 [PubMed - as supplied by publisher]

Correction: DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism.

April 15, 2014 - 8:26am

Correction: DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism.

PLoS Genet. 2014 Apr;10(4):e1004373

Authors: The PLOS Genetics Staff

Abstract
[This corrects the article DOI: 10.1371/journal.pgen.1004241.].

PMID: 24728508 [PubMed - as supplied by publisher]

Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case.

April 15, 2014 - 8:26am
Related Articles

Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case.

Gene. 2014 Apr 1;538(2):373-8

Authors: Palumbo P, Antona V, Palumbo O, Piccione M, Nardello R, Fontana A, Carella M, Corsello G

Abstract
Microdeletions of 17q12 including the hepatocyte nuclear factor 1 beta (HNF1B) gene, as well as point mutations of this gene, are associated with the Renal Cysts and Diabetes syndrome (RCAD, OMIM 137920) and genitourinary alterations. Also, microdeletions encompassing HNF1B were identified as a cause of Mayer-Rokitansky-Küster-Hauser Syndrome (MRKH, OMIM 277000) in females and, recently, were associated with intellectual disability, autistic features, cerebral anomaly and facial dysmorphisms. In this report, we describe a boy with a deletion in 17q12 region detected by SNP array, encompassing the HNF1B gene, that showed dysmorphic features, intellectual disability (ID), serious speech delay and autistic features. In addition, obesity was observed. In order to study the parental origin of the rearrangement, we analyzed selected SNPs in the deleted area in the patient and his parents, showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of maternal origin. Our case confirms the incomplete penetrance and variable expressivity of this deletion, its complex clinical variability, and strengthens the evidence that ID and stereotyped behaviors may be part of the phenotypic spectrum characterizing the affected patients. Also, it is useful to further delineate the phenotypes associated to the deletion being the first case in which obesity has been documented. We present a genotype-phenotype correlation discussing the possible role of some genes, encompassed by the deletion, in the etiology of the observed phenotypes.

PMID: 24487052 [PubMed - indexed for MEDLINE]

Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids.

April 15, 2014 - 8:26am
Related Articles

Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids.

Nutrition. 2013 Oct;29(10):1175-85

Authors: Das UN

Abstract
Autism has a strong genetic and environmental basis in which inflammatory markers and factors concerned with synapse formation, nerve transmission, and information processing such as brain-derived neurotrophic factor (BDNF), polyunsaturated fatty acids (PUFAs): arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) and their products and neurotransmitters: dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and catecholamines and cytokines are altered. Antioxidants, vitamins, minerals, and trace elements are needed for the normal metabolism of neurotrophic factors, eicosanoids, and neurotransmitters, supporting reports of their alterations in autism. But, the exact relationship among these factors and their interaction with genes and proteins concerned with brain development and growth is not clear. It is suggested that maternal infections and inflammation and adverse events during intrauterine growth of the fetus could lead to alterations in the gene expression profile and proteomics that results in dysfunction of the neuronal function and neurotransmitters, alteration(s) in the metabolism of PUFAs and their metabolites resulting in excess production of proinflammatory eicosanoids and cytokines and a deficiency of anti-inflammatory cytokines and bioactive lipids that ultimately results in the development of autism. Based on these evidences, it is proposed that selective delivery of BDNF and methods designed to augment the production of anti-inflammatory cytokines and eicosanoids and PUFAs may prevent, arrest, or reverse the autism disease process.

PMID: 23911220 [PubMed - indexed for MEDLINE]

Focusing on Cause or Cure?: Priorities and Stakeholder Presence in Childhood Psychiatry Research.

April 15, 2014 - 8:26am

Focusing on Cause or Cure?: Priorities and Stakeholder Presence in Childhood Psychiatry Research.

AJOB Prim Res. 2014 Jan 1;5(1):44-55

Authors: Milner LC, Cho MK

Abstract
BACKGROUND: Biomedical research is influenced by many factors, including the involvement of stakeholder groups invested in research outcomes. Stakeholder involvement in research efforts raise questions of justice as their specific interests and motivations play a role in directing research resources that ultimately produce knowledge shaping how different conditions (and affected individuals) are understood and treated by society. This issue is highly relevant to child psychiatry research where diagnostic criteria and treatment strategies are often controversial. Biological similarities and stakeholder differences between attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) provide an opportunity to explore this issue by comparing research foci and stakeholder involvement in these conditions.
METHODS: A subset of ADHD and ASD research articles published between 1970-2010 were randomly selected from the PubMed database and coded for research focus, funding source(s), and author-reported conflicts of interest (COIs). Chi-square analyses were performed to identify differences between and within ADHD and ASD research across time.
RESULTS: The proportion of ADHD research dedicated to basic, description, and treatment research was roughly similar and remained stable over time, while ASD research showed a significant increase in basic research over the past decade. Government was the primary research funder for both conditions, but for-profit funders were a notable presence in ADHD research, while joint-funding efforts between non-profit and government funders were a notable presence in ASD research. Lastly, COIs were noted more frequently in ADHD than in ASD research.
CONCLUSIONS: Our study shows significant differences in research foci and funding sources between the conditions, and identifies the specific involvement of for-profit and non-profit groups in ADHD and ASD, respectively. Our findings highlight the relationship between stakeholders outside the research community and research trajectories and suggest that examinations of these relationships must be included in broader considerations of biomedical research ethics.

PMID: 24729931 [PubMed - as supplied by publisher]

Correction: DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism.

April 15, 2014 - 8:26am

Correction: DUF1220 Dosage Is Linearly Associated with Increasing Severity of the Three Primary Symptoms of Autism.

PLoS Genet. 2014 Apr;10(4):e1004373

Authors: The PLOS Genetics Staff

Abstract
[This corrects the article DOI: 10.1371/journal.pgen.1004241.].

PMID: 24728508 [PubMed - as supplied by publisher]

Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case.

April 15, 2014 - 8:26am
Related Articles

Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case.

Gene. 2014 Apr 1;538(2):373-8

Authors: Palumbo P, Antona V, Palumbo O, Piccione M, Nardello R, Fontana A, Carella M, Corsello G

Abstract
Microdeletions of 17q12 including the hepatocyte nuclear factor 1 beta (HNF1B) gene, as well as point mutations of this gene, are associated with the Renal Cysts and Diabetes syndrome (RCAD, OMIM 137920) and genitourinary alterations. Also, microdeletions encompassing HNF1B were identified as a cause of Mayer-Rokitansky-Küster-Hauser Syndrome (MRKH, OMIM 277000) in females and, recently, were associated with intellectual disability, autistic features, cerebral anomaly and facial dysmorphisms. In this report, we describe a boy with a deletion in 17q12 region detected by SNP array, encompassing the HNF1B gene, that showed dysmorphic features, intellectual disability (ID), serious speech delay and autistic features. In addition, obesity was observed. In order to study the parental origin of the rearrangement, we analyzed selected SNPs in the deleted area in the patient and his parents, showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of maternal origin. Our case confirms the incomplete penetrance and variable expressivity of this deletion, its complex clinical variability, and strengthens the evidence that ID and stereotyped behaviors may be part of the phenotypic spectrum characterizing the affected patients. Also, it is useful to further delineate the phenotypes associated to the deletion being the first case in which obesity has been documented. We present a genotype-phenotype correlation discussing the possible role of some genes, encompassed by the deletion, in the etiology of the observed phenotypes.

PMID: 24487052 [PubMed - indexed for MEDLINE]

Autism, an overwhelming condition: history, etiopathogenesis, types, diagnosis, therapy and prognosis.

April 12, 2014 - 6:51am
Related Articles

Autism, an overwhelming condition: history, etiopathogenesis, types, diagnosis, therapy and prognosis.

Rev Med Chir Soc Med Nat Iasi. 2013 Jul-Sep;117(3):654-61

Authors: Amihăesei IC, Stefanachi E

Abstract
Autism is defined as a neurologic developmental disorder affecting brain and behavior, becoming usually apparent before 3 years of age, with stable evolution and no remission. No neurologic morphologic abnormality was associated with the disease. Several types of disease being described, autism is part of a larger spectrum known as autism spectrum disorders (ASD), or pervasive developmental disorders (PDD). The disease was first described long before it was defined and it has received its modern name. Main cause in the development of autism is considered to be genetic, up to 90 %. However, environmental factors could be incriminated, sometimes. The five types included in ASD are: Asperger syndrome, pervasive developmental disorder-not otherwise specified (PDD-NOS), typical autism, Rett syndrome and childhood disintegrative disorder (CDD). The classical triad of symptoms includes: social interaction impairments, communication impairments and repetitive, stereotype behavior. Diagnosis is based on interview of the parents and specialized observation of the suspected children. Main tools used in therapy are the family and the educational system. Well established, specialized programs of therapy were developed in time. Prognosis of autism is severe, since no cure is possible; nevertheless spontaneous recoveries do occur, in some cases.

PMID: 24502031 [PubMed - indexed for MEDLINE]

The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature.

April 12, 2014 - 6:51am
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The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature.

Autism Res. 2013 Aug;6(4):268-79

Authors: Urraca N, Cleary J, Brewer V, Pivnick EK, McVicar K, Thibert RL, Schanen NC, Esmer C, Lamport D, Reiter LT

Abstract
Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum.

PMID: 23495136 [PubMed - indexed for MEDLINE]

The broad autism phenotype questionnaire: prevalence and diagnostic classification.

April 12, 2014 - 6:51am
Related Articles

The broad autism phenotype questionnaire: prevalence and diagnostic classification.

Autism Res. 2013 Apr;6(2):134-43

Authors: Sasson NJ, Lam KS, Childress D, Parlier M, Daniels JL, Piven J

Abstract
The Broad Autism Phenotype Questionnaire (BAPQ) was administered to a large community-based sample of biological parents of children with autism (PCAs) and comparison parents (CPs) (n = 1,692). Exploratory factor analysis and internal consistency parameters confirmed a robust three-factor structure of the BAPQ, corresponding to the proposed aloof, pragmatic language and rigidity subscales. Based upon the distribution of Broad Autism Phenotype (BAP) features in the general population, new normative cutoff values for BAPQ subscales were established that provide increased specificity relative to those previously reported, and thus enhance the utility of the BAPQ for diagnostically classifying the BAP. These cutoffs were also used to estimate prevalence of the BAP and its three components, with rates ranging between 14-23% for PCAs and between 5-9% for CPs. Analysis of patterns of BAP characteristics within family members revealed that BAP features were more likely to co-occur in PCAs relative to CPs. Collectively, these findings extend the utility of the BAPQ and provide additional evidence that it is an efficient and reliable tool for disaggregating the heterogeneity of autism through the identification of meaningful subgroups of parents. Autism Res 2013, 6: 134-143. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 23427091 [PubMed - indexed for MEDLINE]

Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.

April 10, 2014 - 6:21am

Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.

Mol Syndromol. 2014 Feb;5(2):65-75

Authors: Zink AM, Wohlleber E, Engels H, Rødningen OK, Ravn K, Heilmann S, Rehnitz J, Katzorke N, Kraus C, Blichfeldt S, Hoffmann P, Reutter H, Brockschmidt FF, Kreiß-Nachtsheim M, Vogt PH, Prescott TE, Tümer Z, Lee JA

Abstract
Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.

PMID: 24715853 [PubMed]

Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: Further delineation of an emerging syndrome.

April 10, 2014 - 6:21am

Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: Further delineation of an emerging syndrome.

Am J Med Genet A. 2014 Apr 8;

Authors: Cafferkey M, Ahn JW, Flinter F, Ogilvie C

Abstract
15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome region have recently been linked to a range of neurodevelopment disorders including intellectual disability, speech and language delay, motor delay, autism spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605 patients referred for diagnostic cytogenetic testing found that 83 patients (0.57%) carried the 15q11.2(BP1-BP2) deletion. Phenotypic frequencies in the deleted cohort (n = 83) were compared with frequencies in the non-deleted cohort (n = 14,522); developmental delay, motor delay, and speech and language delay were all more prevalent in the deleted cohort. Notably, motor delay was significantly more common (OR = 6.37). These data indicate that developmental delay, motor delay, and speech and language delay are common clinical features associated with this deletion, providing substantial evidence to support this CNV as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 Wiley Periodicals, Inc.

PMID: 24715682 [PubMed - as supplied by publisher]

The role of AUTS2 in neurodevelopment and human evolution.

April 10, 2014 - 6:21am
Related Articles

The role of AUTS2 in neurodevelopment and human evolution.

Trends Genet. 2013 Oct;29(10):600-8

Authors: Oksenberg N, Ahituv N

Abstract
The autism susceptibility candidate 2 (AUTS2) gene is associated with multiple neurological diseases, including autism, and has been implicated as an important gene in human-specific evolution. Recent functional analysis of this gene has revealed a potential role in neuronal development. Here, we review the literature regarding AUTS2, including its discovery, expression, association with autism and other neurological and non-neurological traits, implication in human evolution, function, regulation, and genetic pathways. Through progress in clinical genomic analysis, the medical importance of this gene is becoming more apparent, as highlighted in this review, but more work needs to be done to discover the precise function and the genetic pathways associated with AUTS2.

PMID: 24008202 [PubMed - indexed for MEDLINE]

Human genetics: Autism - clues from brains and protein domains.

April 9, 2014 - 8:52am

Human genetics: Autism - clues from brains and protein domains.

Nat Rev Genet. 2014 Apr 8;

Authors: Jones B

PMID: 24709752 [PubMed - as supplied by publisher]

Neuropsychological phenotype of a patient with a de novo 970 kb interstitial deletion in the distal 16p11.2 region.

April 8, 2014 - 8:15am

Neuropsychological phenotype of a patient with a de novo 970 kb interstitial deletion in the distal 16p11.2 region.

Neuropsychiatr Dis Treat. 2014;10:513-7

Authors: Egger JI, Verhoeven WM, Verbeeck W, de Leeuw N

Abstract
The 16p11.2 microdeletion syndrome is characterized by a wide range of phenotypic expressions and is frequently associated with developmental delay, symptoms from the autism spectrum, epilepsy, congenital anomalies, and obesity. These phenotypes are often related to a proximal 16p11.2 deletion of approximately 600 kb (BP4-BP5) that includes the SH2B1 gene that is reported to be causative for morbid obesity. This more centromeric deletion is most strongly related to autism spectrum susceptibility and is functionally different from the more distal 16p12.2p11.2 region, which includes the so-called atypical 16p11.2 BP2-BP3 deletion (approximately 220 kb) presenting with developmental delay, behavioral problems and mild facial dysmorphisms. Here, an adult male with a long history of maladaptive behaviors is described who was referred for diagnostic assessment of his amotivational features. Extensive neuropsychological examination demonstrated rigid thinking, anxious beliefs, and ideas of reference in the presence of normal intelligence. Microarray analysis demonstrated a de novo 970 kb 16p11.2 BP1-BP4 microdeletion that can be regarded as explanatory for his behavioral profile. It is concluded that microdeletion syndromes are not exclusively related to intellectual disabilities and genetic testing is of putative relevance for the understanding of neuropsychiatric and neuropsychological phenomena.

PMID: 24707176 [PubMed]

Phenotype-Based Genetic Association Studies (PGAS)-Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes.

April 8, 2014 - 8:15am

Phenotype-Based Genetic Association Studies (PGAS)-Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes.

Genes (Basel). 2014;5(1):97-105

Authors: Ehrenreich H, Nave KA

Abstract
Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these "umbrella diagnoses", genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. "Risk genotypes" of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease) phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS ("phenotype-based genetic association studies"). Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics.

PMID: 24705289 [PubMed]

KASHing up with the nucleus: novel functional roles of KASH proteins at the cytoplasmic surface of the nucleus.

April 8, 2014 - 8:15am

KASHing up with the nucleus: novel functional roles of KASH proteins at the cytoplasmic surface of the nucleus.

Curr Opin Cell Biol. 2014 Apr 3;28C:69-75

Authors: Luxton GG, Starr DA

Abstract
Nuclear-cytoskeletal connections are central to fundamental cellular processes, including nuclear positioning and chromosome movements in meiosis. The cytoskeleton is coupled to the nucleoskeleton through conserved KASH-SUN bridges, or LINC complexes, that span the nuclear envelope. KASH proteins localize to the outer nuclear membrane where they connect the nucleus to the cytoskeleton. New findings have expanded the functional diversity of KASH proteins, showing that they interact with microtubule motors, actin, intermediate filaments, a nonconventional myosin, RanGAP, and each other. The role of KASH proteins in cellular mechanics is discussed. Genetic mutations in KASH proteins are associated with autism, hearing loss, cancer, muscular dystrophy and other diseases.

PMID: 24704701 [PubMed - as supplied by publisher]

An Update on the Hypothesis that One Cause of Autism is High Intrauterine Levels of Testosterone of Maternal Origin.

April 8, 2014 - 8:15am

An Update on the Hypothesis that One Cause of Autism is High Intrauterine Levels of Testosterone of Maternal Origin.

J Theor Biol. 2014 Apr 1;

Authors: James WH

Abstract
Baron-Cohen's hypothesis that autism is caused by exposure to high intrauterine testosterone levels is considered in the context of (1) my hormonal hypothesis of sex ratio and (2) the notion of multifactorial inheritance. This yields the suggestions that 1. Female cases of autism may be the product of (high genetic loading+moderate environmental exposure) and male cases of (high environmental exposure+moderate genetic loading) and that 2. One environmental agent is intrauterine testosterone and that 3. The mother is the major source of that testosterone. These suggestions may help to explain most of the major established epidemiological risk factors for autism. These include various forms of pathology associated with psychological and/or physical stress. Stress of many sorts promotes the secretion of adrenal androgens in women. The three suggestions above may also explain some recently described features of autism including the psychological, behavioural and neuroanatomical differences between male and female cases.

PMID: 24703983 [PubMed - as supplied by publisher]

The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.

April 8, 2014 - 8:15am
Related Articles

The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation.

Exp Neurol. 2014 Mar;253:126-37

Authors: Grabrucker S, Proepper C, Mangus K, Eckert M, Chhabra R, Schmeisser MJ, Boeckers TM, Grabrucker AM

Abstract
Recently, mutations in ProSAP2/Shank3 have been discovered as one of the genetic factors for schizophrenia (SCZ). Here, we show that the postsynaptic density protein ProSAP2/Shank3 undergoes activity dependent synapse-to-nucleus shuttling in hippocampal neurons. Our study shows that the de novo mutation (R1117X) in ProSAP2/Shank3 that was identified in a patient with SCZ leads to an accumulation of mutated ProSAP2/Shank3 within the nucleus independent of synaptic activity. Furthermore, we identified novel nuclear ProSAP2/Shank3 interaction partners. Nuclear localization of mutated ProSAP2/Shank3 alters transcription of several genes, among them already identified genetic risk factors for SCZ such as Synaptotagmin 1 and LRRTM1. Comparing the SCZ mutation of ProSAP2/Shank3 to the knockdown of ProSAP2/Shank3 we found some shared features such as reduced synaptic density in neuronal cultures. However, hippocampal neurons expressing the ProSAP2/Shank3 SCZ mutation furthermore show altered E/I ratio and reduced dendritic branching. Thus, we conclude that the uncoupling of ProSAP2/Shank3 nuclear shuttling from synaptic activity may represent a molecular mechanism that contributes to the pathology of SCZ in patients with mutations in ProSAP2/Shank3.

PMID: 24382453 [PubMed - indexed for MEDLINE]

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