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Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

May 14, 2016 - 7:23am
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Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder.

PLoS One. 2015;10(8):e0134572

Authors: Brunner D, Kabitzke P, He D, Cox K, Thiede L, Hanania T, Sabath E, Alexandrov V, Saxe M, Peles E, Mills A, Spooren W, Ghosh A, Feliciano P, Benedetti M, Luo Clayton A, Biemans B

Abstract
Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.

PMID: 26273832 [PubMed - indexed for MEDLINE]

A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors.

May 14, 2016 - 7:23am
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A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors.

Neural Dev. 2015;10:18

Authors: Zou D, McSweeney C, Sebastian A, Reynolds DJ, Dong F, Zhou Y, Deng D, Wang Y, Liu L, Zhu J, Zou J, Shi Y, Albert I, Mao Y

Abstract
BACKGROUND: Nonsense mediated mRNA decay (NMD) is an RNA surveillance mechanism that controls RNA stability and ensures the speedy degradation of erroneous and unnecessary transcripts. This mechanism depends on several core factors in the exon junction complex (EJC), eIF4A3, RBM8a, Magoh, and BTZ, as well as peripheral factors to distinguish premature stop codons (PTCs) from normal stop codons in transcripts. Recently, emerging evidence has indicated that NMD factors are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the mechanism in which these factors control embryonic brain development is not clear.
RESULT: We found that RBM8a is critical for proliferation and differentiation in cortical neural progenitor cells (NPCs). RBM8a is highly expressed in the subventricular zone (SVZ) of the early embryonic cortex, suggesting that RBM8a may play a role in regulating NPCs. RBM8a overexpression stimulates embryonic NPC proliferation and suppresses neuronal differentiation. Conversely, knockdown of RBM8a in the neocortex reduces NPC proliferation and promotes premature neuronal differentiation. Moreover, overexpression of RBM8a suppresses cell cycle exit and keeps cortical NPCs in a proliferative state. To uncover the underlying mechanisms of this phenotype, genome-wide RNAseq was used to identify potential downstream genes of RBM8a in the brain, which have been implicated in autism and neurodevelopmental disorders. Interestingly, autism and schizophrenia risk genes are highly represented in downstream transcripts of RBM8a. In addition, RBM8a regulates multiple alternative splicing genes and NMD targets that are implicated in ASD. Taken together, this data suggests a novel role of RBM8a in the regulation of neurodevelopment.
CONCLUSIONS: Our studies provide some insight into causes of mental illnesses and will facilitate the development of new therapeutic strategies for neurodevelopmental illnesses.

PMID: 26094033 [PubMed - indexed for MEDLINE]

Biological factors underlying sex differences in neurological disorders.

May 14, 2016 - 7:23am
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Biological factors underlying sex differences in neurological disorders.

Int J Biochem Cell Biol. 2015 Aug;65:139-50

Authors: Loke H, Harley V, Lee J

Abstract
The prevalence, age of onset, pathophysiology, and symptomatology of many neurological and neuropsychiatric conditions differ significantly between males and females. Females suffer more from mood disorders such as depression and anxiety, whereas males are more susceptible to deficits in the dopamine system including Parkinson's disease (PD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and autism spectrum disorders (ASD). Until recently, these sex differences have been explained solely by the neuroprotective actions of sex hormones in females. Emerging evidence however indicates that the sex chromosome genes (i.e. X- and Y-linked genes) also contribute to brain sex differences. In particular, the Y-chromosome gene, SRY (Sex-determining Region on the Y chromosome) is an interesting candidate as it is expressed in dopamine-abundant brain regions, where it regulates dopamine biosynthesis and dopamine-mediated functions such as voluntary movement in males. Furthermore, SRY expression is dysregulated in a toxin-induced model of PD, suggesting a role for SRY in the pathogenesis of dopamine cells. Taken together, these studies highlight the importance of understanding the interplay between sex-specific hormones and sex-specific genes in healthy and diseased brain. In particular, better understanding of regulation and function of SRY in the male brain could provide entirely novel and important insights into genetic factors involved in the susceptibility of men to neurological disorders, as well as development of novel sex-specific therapies.

PMID: 26028290 [PubMed - indexed for MEDLINE]

LAMB1 polymorphism is associated with autism symptom severity in Korean autism spectrum disorder patients.

May 14, 2016 - 7:23am
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LAMB1 polymorphism is associated with autism symptom severity in Korean autism spectrum disorder patients.

Nord J Psychiatry. 2015;69(8):594-8

Authors: Kim YJ, Park JK, Kang WS, Kim SK, Park HJ, Nam M, Kim JW

Abstract
BACKGROUND: LAMB1 encodes laminin beta-1, which is expressed during early development of the human nervous system, and could be involved in the pathogenesis of neurodevelopmental disorders.
AIMS: In our study, we aimed to investigate whether single nucleotide polymorphisms (SNPs) in LAMB1 were associated with autism spectrum disorder (ASD) and with related clinical severities of ASD.
METHODS: Two coding SNPs (rs20556 and rs25659) and two intronic SNPs (rs2158836 and rs2237659) were compared between 180 patients with ASD and 147 healthy control subjects using direct sequencing. The Korean version of the Childhood Autism Rating Scale (K-CARS) was used to assess clinical severities. Multiple logistic regression models were employed to analyze genetic data, and associations with symptom severity were tested with the Kruskal-Wallis and the Mann-Whitney U tests.
RESULTS: None of the four examined SNPs was associated with ASD risk. However, the GG genotype of rs2158836 was associated with more severe symptoms for the "object use" and "non-verbal communication" measures.
CONCLUSIONS: The results of our study suggest the association between rs2158836 polymorphisms and symptom severity in ASD.

PMID: 25774865 [PubMed - indexed for MEDLINE]

Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV.

May 12, 2016 - 7:17am
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Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV.

Am J Hum Genet. 2016 Jan 7;98(1):45-57

Authors: Duyzend MH, Nuttle X, Coe BP, Baker C, Nickerson DA, Bernier R, Eichler EE

Abstract
Recurrent deletions and duplications at chromosomal region 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses, including intellectual disability, coordination disorder, and language disorder. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent of origin of the 16p11.2 copy-number variant (CNV) and the presence of additional CNVs in 126 families for which detailed phenotype data were available. Among de novo cases, we found a strong maternal bias for the origin of deletions (59/66, 89.4% of cases, p = 2.38 × 10(-11)), the strongest such effect so far observed for a CNV associated with a microdeletion syndrome. In contrast to de novo events, we observed no transmission bias for inherited 16p11.2 CNVs, consistent with a female meiotic hotspot of unequal crossover driving this maternal bias. We analyzed this 16p11.2 CNV cohort for the presence of secondary CNVs and found a significant maternal transmission bias for secondary deletions (32 maternal versus 14 paternal, p = 1.14 × 10(-2)). Of the secondary deletions that disrupted a gene, 82% were either maternally inherited or de novo (p = 4.3 × 10(-3)). Nine probands carry secondary CNVs that disrupt genes associated with autism and/or intellectual disability risk variants. Our findings demonstrate a strong bias toward maternal origin of 16p11.2 de novo deletions as well as a maternal transmission bias for secondary deletions that contribute to the clinical outcome on a background sensitized by the 16p11.2 CNV.

PMID: 26749307 [PubMed - indexed for MEDLINE]

Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant.

May 10, 2016 - 7:07am
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Ack1 is a dopamine transporter endocytic brake that rescues a trafficking-dysregulated ADHD coding variant.

Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15480-5

Authors: Wu S, Bellve KD, Fogarty KE, Melikian HE

Abstract
The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKC-sensitive negative endocytic mechanism, or "endocytic brake," controls DAT plasma membrane stability. However, the molecular basis for the DAT endocytic brake is unknown, and it is unknown whether this braking mechanism is unique to DAT or common to monoamine transporters. Here, we report that the cdc42-activated, nonreceptor tyrosine kinase, Ack1, is a DAT endocytic brake that stabilizes DAT at the plasma membrane and is released in response to PKC activation. Pharmacologic and shRNA-mediated Ack1 silencing enhanced basal DAT internalization and blocked PKC-stimulated DAT internalization, but had no effects on SERT endocytosis. Both cdc42 activation and PKC stimulation converge on Ack1 to control Ack1 activity and DAT endocytic capacity, and Ack1 inactivation is required for stimulated DAT internalization downstream of PKC activation. Moreover, constitutive Ack1 activation is sufficient to rescue the gain-of-function endocytic phenotype exhibited by the ADHD DAT coding variant, R615C. These findings reveal a unique endocytic control switch that is highly specific for DAT. Moreover, the ability to rescue the DAT(R615C) coding variant suggests that manipulating DAT trafficking mechanisms may be a potential therapeutic approach to correct DAT coding variants that exhibit trafficking dysregulation.

PMID: 26621748 [PubMed - indexed for MEDLINE]

Chromatin remodeling gene EZH2 involved in the genetic etiology of autism in Chinese Han population.

May 10, 2016 - 7:07am
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Chromatin remodeling gene EZH2 involved in the genetic etiology of autism in Chinese Han population.

Neurosci Lett. 2016 Jan 1;610:182-6

Authors: Li J, You Y, Yue W, Yu H, Lu T, Wu Z, Jia M, Ruan Y, Liu J, Zhang D, Wang L

Abstract
Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders. Epigenetic factors play a critical role in the etiology of ASD. Enhancer of zest homolog 2 (EZH2), which encodes a histone methyltransferase, plays an important role in the process of chromatin remodeling during neurodevelopment. Further, EZH2 is located in chromosome 7q35-36, which is one of the linkage regions for autism. However, the genetic relationship between autism and EZH2 remains unclear. To investigate the association between EZH2 and autism in Chinese Han population, we performed a family-based association study between autism and three tagged single nucleotide polymorphisms (SNPs) that covered 95.4% of the whole region of EZH2. In the discovery cohort of 239 trios, two SNPs (rs740949 and rs6464926) showed a significant association with autism. To decrease false positive results, we expanded the sample size to 427 trios. A SNP (rs6464926) was significantly associated with autism even after Bonferroni correction (p=0.008). Haplotype G-T (rs740949 and rs6464926) was a risk factor for autism (Z=2.655, p=0.008, Global p=0.024). In silico function prediction for SNPs indicated that these two SNPs might be regulatory SNPs. Expression pattern of EZH2 showed that it is highly expressed in human embryonic brains. In conclusion, our findings demonstrate that EZH2 might contribute to the genetic etiology of autism in Chinese Han population.

PMID: 26552012 [PubMed - indexed for MEDLINE]

Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum disorder.

May 10, 2016 - 7:07am
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Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum disorder.

BMC Psychiatry. 2015;15:256

Authors: Philippe A, Craus Y, Rio M, Bahi-Buisson N, Boddaert N, Malan V, Bonnefont JP, Robel L

Abstract
BACKGROUND: Deletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD). Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.
CASE PRESENTATION: Here, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3. The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.
CONCLUSION: Our present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years.

PMID: 26489495 [PubMed - indexed for MEDLINE]

Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder.

May 8, 2016 - 7:00am

Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder.

Gene. 2016 May 4;

Authors: Coşkun S, Şimşek Ş, Camkurt MA, Çim A, Çelik SB

Abstract
Vitamin D is implicated in several aspects of human physiology, and polymorphisms in the vitamin D receptor gene (VDR) are associated with a variety of neuropsychiatric disorders. The aims of this study are to determine whether VDR polymorphisms are associated with autism spectrum disorder (ASD), to examine serum 25-hydroxyvitamin D (25(OH)D) levels in ASD, and to explore whether VDR polymorphisms influence serum 25(OH)D levels. We investigated 480 subjects (237 children with ASD and 243 healthy controls) for the following VDR polymorphisms: TaqI, BsmI, FokI, ApaI, and Cdx2.Within the same samples, 25(OH)D levels were available only for 85 patients and 82 controls. The Cdx-2 variation was shown to deviate from Hardy-Weinberg equilibrium in the controls and was therefore excluded from the study. We found that the frequency of rare FokI TT, TaqI CC, and BsmI AA genotypes differed significantly between children with ASD and the controls (p=0.042, p=0.016, p=0.038, respectively). After correction for multiple testing, only the TaqI CC genotype remained significant. Further analysis using a recessive model showed that rare genotypes of these polymorphisms were significantly higher in patients compared to controls (p=0.045, p=0.005 and p=0.031, respectively). However, no significant association was found between ApaI and ASD. We found serum 25(OH)D levels to be significantly higher in children with ASD (p<0.001) and that the FokI polymorphism had an effect on serum 25(OH)D levels in children with ASD (p=0.041). Additionally, we found the haplotype GTTT (BsmI/TaqI/FokI/ApaI) conferred an increased risk for developing ASD (p=0.022; odds ratio [95% confidence interval]=2.322 [1.105-4.879]). This is the first clinical study evaluating the association between serum 25(OH)D levels and VDR polymorphisms in children with ASD. Our results demonstrated a significant association between TaqI, BsmI, and FokI polymorphisms and ASD and showed for the first time that FokI polymorphisms and haplotype GTTT (BsmI/TaqI/FokI/ApaI) are associated with an increased risk of ASD. Our findings support the hypothesis that 25(OH)D is involved in the pathophysiology of autism and that serum 25(OH)D levels may be affected by FokI polymorphisms in children with ASD. Our results should be considered as preliminary and needs confirmation by future studies.

PMID: 27155524 [PubMed - as supplied by publisher]

Repetitive Behavioral Assessments for Compound Screening in Mouse Models of Autism Spectrum Disorders.

May 7, 2016 - 9:54am

Repetitive Behavioral Assessments for Compound Screening in Mouse Models of Autism Spectrum Disorders.

Methods Mol Biol. 2016;1438:293-310

Authors: Rizzo SJ

Abstract
Treatments for repetitive behaviors in Autism Spectrum Disorders (ASD) and other neurodevelopmental disorders remain an unmet medical need. Mouse models are highly valuable tools for investigating the underlying pathophysiology, genetics, and neurocircuitry of ASD, and can also be characterized for ASD-related phenotypes including repetitive behaviors and stereotypies. This chapter describes methods that can be employed for the assessment of repetitive behavior phenotypes and the evaluation of the ability of test compounds to attenuate repetitive behaviors in mouse models of ASD.

PMID: 27150097 [PubMed - in process]

Neurodevelopmental disease: A molecular tightrope.

May 7, 2016 - 9:54am
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Neurodevelopmental disease: A molecular tightrope.

Nature. 2015 Oct 1;526(7571):50-1

Authors: Elgersma Y

PMID: 26432241 [PubMed - indexed for MEDLINE]

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

May 7, 2016 - 9:54am
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Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.

Eur J Hum Genet. 2015 Nov;23(11):1482-7

Authors: Bronicki LM, Redin C, Drunat S, Piton A, Lyons M, Passemard S, Baumann C, Faivre L, Thevenon J, Rivière JB, Isidor B, Gan G, Francannet C, Willems M, Gunel M, Jones JR, Gleeson JG, Mandel JL, Stevenson RE, Friez MJ, Aylsworth AS

Abstract
The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

PMID: 25920557 [PubMed - indexed for MEDLINE]

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

May 7, 2016 - 9:54am
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CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

Eur J Hum Genet. 2015 Nov;23(11):1505-12

Authors: Damaj L, Lupien-Meilleur A, Lortie A, Riou É, Ospina LH, Gagnon L, Vanasse C, Rossignol E

Abstract
CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

PMID: 25735478 [PubMed - indexed for MEDLINE]

The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms.

May 7, 2016 - 9:54am
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The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms.

Int J Environ Res Public Health. 2015 Mar;12(3):2465-85

Authors: Gross-Davis CA, Heavner K, Frank AL, Newschaffer C, Klotz J, Santella RM, Burstyn I

Abstract
BACKGROUND: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation--JAK2 V617F--suggesting a potential role for environmental mutagens.
METHODS: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921-1968 and residing in the area between 2000-2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease.
RESULTS: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3-5 fold increased risk.
CONCLUSIONS: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs.

PMID: 25719551 [PubMed - indexed for MEDLINE]

Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

May 6, 2016 - 6:52am

Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

PLoS One. 2016;11(5):e0154864

Authors: Cubells JF, Schroeder JP, Barrie ES, Manvich DF, Sadee W, Berg T, Mercer K, Stowe TA, Liles LC, Squires KE, Mezher A, Curtin P, Perdomo DL, Szot P, Weinshenker D

Abstract
Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency phenotypes, but did not reveal an impact of the rs11115 variant on DBH expression in mice.

PMID: 27148966 [PubMed - as supplied by publisher]

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

May 6, 2016 - 6:52am

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000562

Authors: Yang H, Douglas G, Monaghan KG, Retterer K, Cho MT, Escobar LF, Tucker ME, Stoler J, Rodan LH, Stein D, Marks W, Enns GM, Platt J, Cox R, Wheeler PG, Crain C, Calhoun A, Tryon R, Richard G, Vitazka P, Chung WK

Abstract
Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

PMID: 27148574 [PubMed]

Genome-wide variant analysis of simplex autism families with an integrative clinical-bioinformatics pipeline.

May 6, 2016 - 6:52am

Genome-wide variant analysis of simplex autism families with an integrative clinical-bioinformatics pipeline.

Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000422

Authors: Jiménez-Barrón LT, O'Rawe JA, Wu Y, Yoon M, Fang H, Iossifov I, Lyon GJ

Abstract
Autism spectrum disorders (ASDs) are a group of developmental disabilities that affect social interaction and communication and are characterized by repetitive behaviors. There is now a large body of evidence that suggests a complex role of genetics in ASDs, in which many different loci are involved. Although many current population-scale genomic studies have been demonstrably fruitful, these studies generally focus on analyzing a limited part of the genome or use a limited set of bioinformatics tools. These limitations preclude the analysis of genome-wide perturbations that may contribute to the development and severity of ASD-related phenotypes. To overcome these limitations, we have developed and utilized an integrative clinical and bioinformatics pipeline for generating a more complete and reliable set of genomic variants for downstream analyses. Our study focuses on the analysis of three simplex autism families consisting of one affected child, unaffected parents, and one unaffected sibling. All members were clinically evaluated and widely phenotyped. Genotyping arrays and whole-genome sequencing were performed on each member, and the resulting sequencing data were analyzed using a variety of available bioinformatics tools. We searched for rare variants of putative functional impact that were found to be segregating according to de novo, autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous copy-number variations (CNVs), a rare heterozygous de novo nonsense mutation in MYBBP1A located within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates how more comprehensive analyses that include rich clinical data and whole-genome sequencing data can generate reliable results for use in downstream investigations.

PMID: 27148569 [PubMed]

The quest for targeted therapy in fragile X syndrome.

May 6, 2016 - 6:52am
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The quest for targeted therapy in fragile X syndrome.

Expert Opin Ther Targets. 2015;19(10):1277-81

Authors: Zeidler S, Hukema RK, Willemsen R

Abstract
Fragile X syndrome (FXS) is the most common, monogenetic cause of intellectual disability and autism-spectrum disorders. Although there is no effective therapy, greater understanding of disturbed neuronal pathways has introduced options for targeted therapy. But whereas many FXS phenotypes were improved in preclinical studies with drugs targeting these pathways in the FXS mouse model, attempts to translate these animal-model success stories into treatment of patients in clinical trials have been extremely disappointing. Complicating factors, particularly in animal studies, include mouse inbred strains, variability in functional studies between laboratories, publication bias and lack of reliable and objective primary outcome measures in both mice and patients. Possibly most important, however, is one factor that has been little explored: the complexity of the molecular imbalance in FXS and the need to simultaneously target several different disturbed pathways and different cellular compartments. New, well-conceived animal studies should generate more productive approaches in the quest for targeted therapy for FXS.

PMID: 26294013 [PubMed - indexed for MEDLINE]

Brief report: systematic review of Rett syndrome in males.

May 6, 2016 - 6:52am
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Brief report: systematic review of Rett syndrome in males.

J Autism Dev Disord. 2015 Oct;45(10):3377-83

Authors: Reichow B, George-Puskar A, Lutz T, Smith IC, Volkmar FR

Abstract
Rett syndrome (RTT) is a neurogenetic disorder in which a period of typical development is followed by loss of previously acquired skills. Once thought to occur exclusively in females, increasing numbers of male cases of RTT have been reported. This systematic review included 36 articles describing 57 cases of RTT in males. Mutations of the MECP2 gene were present in 56 % of cases, and 68 % of cases reported other genetic abnormalities. This is the first review of published reports of RTT in male patients.

PMID: 26254891 [PubMed - indexed for MEDLINE]

Tracking social motivation systems deficits: the affective neuroscience view of autism.

May 6, 2016 - 6:52am
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Tracking social motivation systems deficits: the affective neuroscience view of autism.

J Autism Dev Disord. 2015 Oct;45(10):3351-63

Authors: Carré A, Chevallier C, Robel L, Barry C, Maria AS, Pouga L, Philippe A, Pinabel F, Berthoz S

Abstract
Abnormal functioning of primary brain systems that express and modulate basic emotional drives are increasingly considered to underlie mental disorders including autism spectrum disorders. We hypothesized that ASD are characterized by disruptions in the primary systems involved in the motivation for social bonding. Twenty adults with ASD were compared to 20 neurotypical participants on the basis of self-reports and clinical assessments, including the Social Anhedonia Scale (SAS) and the Affective Neuroscience Personality Scales (ANPS). ASD diagnosis was related to SAS, as well as to positive (PLAYFULNESS) and negative (FEAR) ANPS-traits. In the overall sample, levels of autistic traits (AQ) were related to SAS and PLAYFULNESS. We argue that PLAYFULNESS could be at the root of social bonding impairments in ASD.

PMID: 26123007 [PubMed - indexed for MEDLINE]

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