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CACNA1D De Novo Mutations in Autism Spectrum Disorders Activate Cav1.3 L-Type Calcium Channels.

January 27, 2015 - 6:56am

CACNA1D De Novo Mutations in Autism Spectrum Disorders Activate Cav1.3 L-Type Calcium Channels.

Biol Psychiatry. 2014 Dec 8;

Authors: Pinggera A, Lieb A, Benedetti B, Lampert M, Monteleone S, Liedl KR, Tuluc P, Striessnig J

Abstract
BACKGROUND: Cav1.3 voltage-gated L-type calcium channels (LTCCs) are part of postsynaptic neuronal signaling networks. They play a key role in brain function, including fear memory and emotional and drug-taking behaviors. A whole-exome sequencing study identified a de novo mutation, p.A749G, in Cav1.3 α1-subunits (CACNA1D), the second main LTCC in the brain, as 1 of 62 high risk-conferring mutations in a cohort of patients with autism and intellectual disability. We screened all published genetic information available from whole-exome sequencing studies and identified a second de novo CACNA1D mutation, p.G407R. Both mutations are present only in the probands and not in their unaffected parents or siblings.
METHODS: We functionally expressed both mutations in tsA-201 cells to study their functional consequences using whole-cell patch-clamp.
RESULTS: The mutations p.A749G and p.G407R caused dramatic changes in channel gating by shifting (~15 mV) the voltage dependence for steady-state activation and inactivation to more negative voltages (p.A749G) or by pronounced slowing of current inactivation during depolarizing stimuli (p.G407R). In both cases, these changes are compatible with a gain-of-function phenotype.
CONCLUSIONS: Our data, together with the discovery that Cav1.3 gain-of-function causes primary aldosteronism with seizures, neurologic abnormalities, and intellectual disability, suggest that Cav1.3 gain-of-function mutations confer a major part of the risk for autism in the two probands and may even cause the disease. Our findings have immediate clinical relevance because blockers of LTCCs are available for therapeutic attempts in affected individuals. Patients should also be explored for other symptoms likely resulting from Cav1.3 hyperactivity, in particular, primary aldosteronism.

PMID: 25620733 [PubMed - as supplied by publisher]

Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation.

January 27, 2015 - 6:56am
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Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation.

Epilepsia. 2014 Oct;55(10):1558-67

Authors: Ohmori I, Kawakami N, Liu S, Wang H, Miyazaki I, Asanuma M, Michiue H, Matsui H, Mashimo T, Ouchida M

Abstract
OBJECTIVE: Developmental disorders including cognitive deficit, hyperkinetic disorder, and autistic behaviors are frequently comorbid in epileptic patients with SCN1A mutations. However, the mechanisms underlying these developmental disorders are poorly understood and treatments are currently unavailable. Using a rodent model with an Scn1a mutation, we aimed to elucidate the pathophysiologic basis and potential therapeutic treatments for developmental disorders stemming from Scn1a mutations.
METHODS: We conducted behavioral analyses on rats with the N1417H-Scn1a mutation. With high-performance liquid chromatography, we measured dopamine and its metabolites in the frontal cortex, striatum, nucleus accumbens, and midbrain. Methylphenidate was administered intraperitoneally to examine its effects on developmental disorder-like behaviors and hyperthermia-induced seizures.
RESULTS: Behavioral studies revealed that Scn1a-mutant rats had repetitive behavior, hyperactivity, anxiety-like behavior, spatial learning impairments, and motor imbalance. Dopamine levels in the striatum and nucleus accumbens in Scn1a-mutant rats were significantly lower than those in wild-type rats. In Scn1a-mutant rats, methylphenidate, by increasing dopamine levels in the synaptic cleft, improved hyperactivity, anxiety-like behavior, and spatial learning impairments. Surprisingly, methylphenidate also strongly suppressed hyperthermia-induced seizures.
SIGNIFICANCE: Dysfunction of the mesolimbic dopamine reward pathway may contribute to the hyperactivity and learning impairments in Scn1a-mutant rats. Methylphenidate was effective for treating hyperactivity, learning impairments, and hyperthermia-induced seizures. We propose that methylphenidate treatment may ameliorate not only developmental disorders but also epileptic seizures in patients with SCN1A mutations.

PMID: 25154505 [PubMed - indexed for MEDLINE]

Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology.

January 27, 2015 - 6:56am
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Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology.

Am J Med Genet C Semin Med Genet. 2014 Jun;166C(2):156-72

Authors: Mirzaa GM, Poduri A

Abstract
Megalencephaly (MEG) is a developmental disorder characterized by brain overgrowth that occurs due to either increased number or size of neurons and glial cells. The former may be due to either increased neuronal proliferation or decreased apoptosis. The degree of brain overgrowth may be extensive, ranging from generalized MEG affecting the entire cortex-as with mutations in PTEN (phosphatase and tensin homolog on chromosome ten)-to unilateral hemispheric malformations-as in classic hemimegalencephaly (HME). On the other hand, some lesions are more focal or segmental. These developmental brain abnormalities may occur in isolation in some individuals, whereas others occur in the context of a syndrome involving dysmorphic features, skin findings, or other organ system involvement. Brain overgrowth disorders are often associated with malformations of cortical development, resulting in increased risk of epilepsy, intellectual disability, and autistic features, and some are associated with hydrocephalus. The past few years have witnessed a dramatic leap in our understanding of the molecular basis of brain overgrowth, particularly the identification of mosaic (or post-zygotic) mutations in core components of key cellular pathways such as the phosphatidylinositol 3-kinase (PI3K)-vakt murine thymoma viral oncogene homolog (AKT)-mTOR pathway. These molecular insights have broadened our view of brain overgrowth disorders that now appear to span a wide spectrum of overlapping phenotypic, neuroimaging, and neuropathologic features and molecular pathogenesis. These molecular advances also bring to light the possibility of pathway-based therapies for these often medically devastating developmental disorders.

PMID: 24888963 [PubMed - indexed for MEDLINE]

Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation.

January 27, 2015 - 6:56am
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Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation.

Hum Mol Genet. 2014 Jul 1;23(13):3481-9

Authors: Lee H, Lin MC, Kornblum HI, Papazian DM, Nelson SF

Abstract
Numerous studies and case reports show comorbidity of autism and epilepsy, suggesting some common molecular underpinnings of the two phenotypes. However, the relationship between the two, on the molecular level, remains unclear. Here, whole exome sequencing was performed on a family with identical twins affected with autism and severe, intractable seizures. A de novo variant was identified in the KCND2 gene, which encodes the Kv4.2 potassium channel. Kv4.2 is a major pore-forming subunit in somatodendritic subthreshold A-type potassium current (ISA) channels. The de novo mutation p.Val404Met is novel and occurs at a highly conserved residue within the C-terminal end of the transmembrane helix S6 region of the ion permeation pathway. Functional analysis revealed the likely pathogenicity of the variant in that the p.Val404Met mutant construct showed significantly slowed inactivation, either by itself or after equimolar coexpression with the wild-type Kv4.2 channel construct consistent with a dominant effect. Further, the effect of the mutation on closed-state inactivation was evident in the presence of auxiliary subunits that associate with Kv4 subunits to form ISA channels in vivo. Discovery of a functionally relevant novel de novo variant, coupled with physiological evidence that the mutant protein disrupts potassium current inactivation, strongly supports KCND2 as the causal gene for epilepsy in this family. Interaction of KCND2 with other genes implicated in autism and the role of KCND2 in synaptic plasticity provide suggestive evidence of an etiological role in autism.

PMID: 24501278 [PubMed - indexed for MEDLINE]

Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests.

January 27, 2015 - 6:56am
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Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests.

Hum Mol Genet. 2014 Jul 1;23(13):3490-505

Authors: Clipperton-Allen AE, Page DT

Abstract
Accelerated head and brain growth (macrocephaly) during development is a replicated biological finding in a subset of individuals with autism spectrum disorder (ASD). However, the relationship between brain overgrowth and the behavioral and cognitive symptoms of ASD is poorly understood. The PI3K-Akt-mTOR pathway regulates cellular growth; several genes encoding negative regulators of this pathway are ASD risk factors, including PTEN. Mutations in PTEN have been reported in individuals with ASD and macrocephaly. We report that brain overgrowth is widespread in Pten germline haploinsufficient (Pten(+/-)) mice, reflecting Pten mRNA expression in the developing brain. We then ask if broad brain overgrowth translates into general or specific effects on the development of behavior and cognition by testing Pten(+/-) mice using assays relevant to ASD and comorbidities. Deficits in social behavior were observed in both sexes. Males also showed abnormalities related to repetitive behavior and mood/anxiety. Females exhibited circadian activity and emotional learning phenotypes. Widespread brain overgrowth together with selective behavioral impairments in Pten(+/-) mice raises the possibility that most brain areas and constituent cell types adapt to an altered trajectory of growth with minimal impact on the behaviors tested in our battery; however, select areas/cell types relevant to social behavior are more vulnerable or less adaptable, thus resulting in social deficits. Probing dopaminergic neurons as a candidate vulnerable cell type, we found social behavioral impairments in mice with Pten conditionally inactivated in dopaminergic neurons that are consistent with the possibility that desynchronized growth in key cell types may contribute to ASD endophenotypes.

PMID: 24497577 [PubMed - indexed for MEDLINE]

Distal trisomy 10q syndrome, report of a patient with duplicated q24.31 - qter, autism spectrum disorder and unusual features.

January 24, 2015 - 7:59am

Distal trisomy 10q syndrome, report of a patient with duplicated q24.31 - qter, autism spectrum disorder and unusual features.

Clin Case Rep. 2014 Oct;2(5):201-5

Authors: Al-Sarraj Y, Al-Khair HA, Taha RZ, Khattab N, El Sayed ZH, Elhusein B, El-Shanti H

Abstract
KEY CLINICAL MESSAGE: We report on a patient with distal trisomy 10q syndrome presenting with a few previously undescribed physical features, as well as, autism spectrum disorder (ASD). We recommend that patients with distal trisomy 10q syndrome should have a behavioral evaluation for ASD for the early institution of therapy.

PMID: 25614812 [PubMed]

Epigenetics as a basis for diagnosis of neurodevelopmental disorders: challenges and opportunities.

January 24, 2015 - 7:59am
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Epigenetics as a basis for diagnosis of neurodevelopmental disorders: challenges and opportunities.

Expert Rev Mol Diagn. 2014 Jul;14(6):685-97

Authors: Kubota T, Miyake K, Hariya N, Mochizuki K

Abstract
Neurodevelopmental disorders, such as autism, are complex entities that can be caused by biological and social factors. In a subset of patients with congenital neurodevelopmental disorders, clear diagnosis can be achieved using DNA sequence-based analysis to identify changes in the DNA sequence (genetic variation). However, it has recently become clear that changes to the secondary modifications of DNA and histone structures (epigenetic variation) can also cause neurodevelopmental disorders via alteration of neural gene function. Moreover, it has recently been demonstrated that epigenetic modifications are more susceptible to alterations induced by environmental factors than are DNA sequences, and that some drugs commonly used reverse mental-stress induced alterations to histone modifications in neural genes. Therefore, application of diagnostic assays to detect epigenetic alterations will provide new insight into the characterization and treatment of neurodevelopmental disorders.

PMID: 24902600 [PubMed - indexed for MEDLINE]

A prenatal case of split-hand malformation associated with 17p13.3 triplication - a dilemma in genetic counseling.

January 24, 2015 - 7:59am
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A prenatal case of split-hand malformation associated with 17p13.3 triplication - a dilemma in genetic counseling.

Eur J Med Genet. 2014 Feb;57(2-3):81-4

Authors: Luk HM, Wong VC, Lo IF, Chan KY, Lau ET, Kan AS, Tang MH, Tang WF, She WM, Chu YW, Sin WK, Chung BH

Abstract
Copy number gain of 17p13.3 has been shown to be associated with developmental delay/autism and Split-Hand-Foot malformation. We report a case of fetus with bilateral split-hand malformation detected on prenatal ultrasound. Array comparative genomic hybridization detected 2 maternally inherited copy number gains in the 17p13.3 region with one of them involving the BHLHA9 gene and part of the YWHAE gene. The mother is normal in intelligence with mild right foot anomaly only. Although the BHLHA9 copy gain is known to be associated with split-hand-foot malformation, the penetrance and expressivity is highly variable. More challenging is the effect of partial YWHAE copy number gain on neurodevelopment is inconclusive based on current literature. This case highlights the difficulties of prenatal genetic counseling in array comparative genomic hybridization findings in clinical situation with incomplete understanding of genotype-phenotype correlation.

PMID: 24380768 [PubMed - indexed for MEDLINE]

Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice.

January 23, 2015 - 7:45am

Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice.

Brain Sci. 2015;5(1):3-13

Authors: Mizuno A, Cherepanov SM, Kikuchi Y, Fakhrul AA, Akther S, Deguchi K, Yoshihara T, Ishihara K, Shuto S, Higashida H

Abstract
Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson's disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.

PMID: 25612002 [PubMed - as supplied by publisher]

Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism.

January 23, 2015 - 7:45am

Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism.

Sci Transl Med. 2015 Jan 21;7(271):271ra8

Authors: Peñagarikano O, Lázaro MT, Lu XH, Gordon A, Dong H, Lam HA, Peles E, Maidment NT, Murphy NP, Yang XW, Golshani P, Geschwind DH

Abstract
Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.

PMID: 25609168 [PubMed - in process]

Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.

January 23, 2015 - 7:45am
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Assessing the impact of copy number variants on miRNA genes in autism by Monte Carlo simulation.

PLoS One. 2014;9(3):e90947

Authors: Marrale M, Albanese NN, Calì F, Romano V

Abstract
Autism Spectrum Disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies have investigated the role of de novo Copy Number Variants (CNVs) and microRNAs as important but distinct etiological factors in ASD. We developed a novel computational procedure to assess the potential pathogenic role of microRNA genes overlapping de novo CNVs in ASD patients. Here we show that for chromosomes # 1, 2 and 22 the actual number of miRNA loci affected by de novo CNVs in patients was found significantly higher than that estimated by Monte Carlo simulation of random CNV events. Out of 24 miRNA genes over-represented in CNVs from these three chromosomes only hsa-mir-4436b-1 and hsa-mir-4436b-2 have not been detected in CNVs from non-autistic subjects as reported in the Database of Genomic Variants. Altogether the results reported in this study represent a first step towards a full understanding of how a dysregulated expression of the 24 miRNAs genes affect neurodevelopment in autism. We also propose that the procedure used in this study can be effectively applied to CNVs/miRNA genes association data in other genomic disorders beyond autism.

PMID: 24667286 [PubMed - indexed for MEDLINE]

Origin and loss of nested LRRTM/α-catenin genes during vertebrate evolution.

January 23, 2015 - 7:45am
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Origin and loss of nested LRRTM/α-catenin genes during vertebrate evolution.

PLoS One. 2014;9(2):e89910

Authors: Uvarov P, Kajander T, Airaksinen MS

Abstract
Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) form in mammals a family of four postsynaptic adhesion proteins, which have been shown to bind neurexins and heparan sulphate proteoglycan (HSPG) glypican on the presynaptic side. Mutations in the genes encoding LRRTMs and neurexins are implicated in human cognitive disorders such as schizophrenia and autism. Our analysis shows that in most jawed vertebrates, lrrtm1, lrrtm2, and lrrtm3 genes are nested on opposite strands of large conserved intron of α-catenin genes ctnna2, ctnna1, and ctnna3, respectively. No lrrtm genes could be found in tunicates or lancelets, while two lrrtm genes are found in the lamprey genome, one of which is adjacent to a single ctnna homolog. Based on similar highly positive net charge of lamprey LRRTMs and the HSPG-binding LRRTM3 and LRRTM4 proteins, we speculate that the ancestral LRRTM might have bound HSPG before acquiring neurexins as binding partners. Our model suggests that lrrtm gene translocated into the large ctnna intron in early vertebrates, and that subsequent duplications resulted in three lrrtm/ctnna gene pairs present in most jawed vertebrates. However, we detected three prominent exceptions: (1) the lrrtm3/ctnna3 gene structure is absent in the ray-finned fish genomes, (2) the genomes of clawed frogs contain ctnna1 but lack the corresponding nested (lrrtm2) gene, and (3) contain lrrtm3 gene in the syntenic position but lack the corresponding host (ctnna3) gene. We identified several other protein-coding nested gene structures of which either the host or the nested gene has presumably been lost in the frog or chicken lineages. Interestingly, majority of these nested genes comprise LRR domains.

PMID: 24587117 [PubMed - indexed for MEDLINE]

Parent-delivered touchscreen intervention for children with fragile X syndrome.

January 22, 2015 - 7:07am

Parent-delivered touchscreen intervention for children with fragile X syndrome.

Intractable Rare Dis Res. 2014 Nov;3(4):166-77

Authors: Díez-Juan M, Schneider A, Phillips T, Lozano R, Tassone F, Solomon M, Hagerman RJ

Abstract
The use of touchscreen applications for the iPad(®) allows children with disabilities to improve their personal autonomy and quality of life. In light of this emerging literature and our clinical experience with toddlers and children with Fragile X syndrome (FXS), a randomized clinical trial pilot study was conducted of whether an interactive iPad(®)-based parent training program was efficacious for both individuals with FXS and autism spectrum disorder aged 2-to-12 compared to wait-listed controls. As a second goal, we assessed the difference between direct person-to-person therapy vs. online therapy sessions through telehealth. In this case series report it is presented preliminary results of four individuals with FXS enrolled in the study and described the innovative experience including qualitative and quantitative data analysis. Furthermore, we provide professionals with specific guidelines about the use of touchscreen devices as in-home learning tools and parent training strategies to actively involve families in educational treatments in conjunction with clinical guidance.

PMID: 25606367 [PubMed]

Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability.

January 22, 2015 - 7:07am

Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability.

Mol Cytogenet. 2014;7(1):97

Authors: Kashevarova AA, Nazarenko LP, Schultz-Pedersen S, Skryabin NA, Salyukova OA, Chechetkina NN, Tolmacheva EN, Rudko AA, Magini P, Graziano C, Romeo G, Joss S, Tümer Z, Lebedev IN

Abstract
BACKGROUND: Detection of submicroscopic chromosomal alterations in patients with a idiopathic intellectual disability (ID) allows significant improvement in delineation of the regions of the genome that are associated with brain development and function. However, these chromosomal regions usually contain several protein-coding genes and regulatory elements, complicating the understanding of genotype-phenotype correlations. We report two siblings with ID and an unrelated patient with atypical autism who had 3p26.3 microdeletions and one intellectually disabled patient with a 3p26.3 microduplication encompassing only the CNTN6 gene.
RESULTS: Two 295.1-kb microdeletions and one 766.1-kb microduplication of 3p26.3 involving a single gene, CNTN6, were identified with an Agilent 60K array. Another 271.9-kb microdeletion of 3p26.3 was detected using an Affymetrix CytoScan HD chromosome microarray platform. The CHL1 and CNTN4 genes, although adjacent to the CNTN6 gene, were not affected in either of these patients.
CONCLUSIONS: The protein encoded by CNTN6 is a member of the immunoglobulin superfamily and functions as a cell adhesion molecule that is involved in the formation of axon connections in the developing nervous system. Our results indicate that CNTN6 may be a candidate gene for ID.

PMID: 25606055 [PubMed]

Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses.

January 22, 2015 - 7:07am
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Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapses.

Neuron. 2014 Oct 22;84(2):399-415

Authors: Smith KR, Kopeikina KJ, Fawcett-Patel JM, Leaderbrand K, Gao R, Schürmann B, Myczek K, Radulovic J, Swanson GT, Penzes P

Abstract
Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in the ANK3 gene, encoding ankyrin-G, have been associated with bipolar disorder, schizophrenia, and autism. Here we demonstrate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. Using superresolution microscopy we find that ankyrin-G forms distinct nanodomain structures within the spine head and neck. At these sites, it modulates mushroom spine structure and function, probably as a perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes ankyrin-G accumulation in distinct spine subdomains, where it differentially regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic nanodomains containing a major psychiatric risk molecule, ankyrin-G, as having location-specific functions and open directions for basic and translational investigation of psychiatric risk molecules.

PMID: 25374361 [PubMed - indexed for MEDLINE]

Adult neuropsychiatric expression and familial segregation of 2q13 duplications.

January 22, 2015 - 7:07am
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Adult neuropsychiatric expression and familial segregation of 2q13 duplications.

Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):337-44

Authors: Costain G, Lionel AC, Fu F, Stavropoulos DJ, Gazzellone MJ, Marshall CR, Scherer SW, Bassett AS

Abstract
New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later-onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression.

PMID: 24807792 [PubMed - indexed for MEDLINE]

Maternally inherited genetic variants of CADPS2 are present in autism spectrum disorders and intellectual disability patients.

January 22, 2015 - 7:07am
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Maternally inherited genetic variants of CADPS2 are present in autism spectrum disorders and intellectual disability patients.

EMBO Mol Med. 2014 Jun;6(6):795-809

Authors: Bonora E, Graziano C, Minopoli F, Bacchelli E, Magini P, Diquigiovanni C, Lomartire S, Bianco F, Vargiolu M, Parchi P, Marasco E, Mantovani V, Rampoldi L, Trudu M, Parmeggiani A, Battaglia A, Mazzone L, Tortora G, IMGSAC, Maestrini E, Seri M, Romeo G

Abstract
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.

PMID: 24737869 [PubMed - indexed for MEDLINE]

Disruption of Transient Serotonin Accumulation by Non-Serotonin-Producing Neurons Impairs Cortical Map Development.

January 21, 2015 - 6:29am

Disruption of Transient Serotonin Accumulation by Non-Serotonin-Producing Neurons Impairs Cortical Map Development.

Cell Rep. 2015 Jan 14;

Authors: Chen X, Ye R, Gargus JJ, Blakely RD, Dobrenis K, Sze JY

Abstract
Polymorphisms that alter serotonin transporter SERT expression and functionality increase the risks for autism and psychiatric traits. Here, we investigate how SERT controls serotonin signaling in developing CNS in mice. SERT is transiently expressed in specific sets of glutamatergic neurons and uptakes extrasynaptic serotonin during perinatal CNS development. We show that SERT expression in glutamatergic thalamocortical axons (TCAs) dictates sensory map architecture. Knockout of SERT in TCAs causes lasting alterations in TCA patterning, spatial organizations of cortical neurons, and dendritic arborization in sensory cortex. Pharmacological reduction of serotonin synthesis during the first postnatal week rescues sensory maps in SERT(GluΔ) mice. Furthermore, knockdown of SERT expression in serotonin-producing neurons does not impair barrel maps. We propose that spatiotemporal SERT expression in non-serotonin-producing neurons represents a determinant in early life genetic programming of cortical circuits. Perturbing this SERT function could be involved in the origin of sensory and cognitive deficits associated with neurodevelopmental disorders.

PMID: 25600870 [PubMed - as supplied by publisher]

Hippocampal dysregulation of neurofibromin-dependent pathways is associated with impaired spatial learning in engrailed 2 knock-out mice.

January 21, 2015 - 6:29am
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Hippocampal dysregulation of neurofibromin-dependent pathways is associated with impaired spatial learning in engrailed 2 knock-out mice.

J Neurosci. 2014 Oct 1;34(40):13281-8

Authors: Provenzano G, Pangrazzi L, Poli A, Pernigo M, Sgadò P, Genovesi S, Zunino G, Berardi N, Casarosa S, Bozzi Y

Abstract
Genome-wide association studies indicated the homeobox-containing transcription factor Engrailed-2 (En2) as a candidate gene for autism spectrum disorders (ASD). Accordingly, En2 knock-out (En2(-/-)) mice show anatomical and behavioral "ASD-like" features, including decreased sociability and learning deficits. The molecular pathways underlying these deficits in En2(-/-) mice are not known. Deficits in signaling pathways involving neurofibromin and extracellular-regulated kinase (ERK) have been associated with impaired learning. Here we investigated the neurofibromin-ERK cascade in the hippocampus of wild-type (WT) and En2(-/-) mice before and after spatial learning testing. When compared with WT littermates, En2(-/-) mice showed impaired performance in the Morris water maze (MWM), which was accompanied by lower expression of the activity-dependent gene Arc. Quantitative RT-PCR, immunoblotting, and immunohistochemistry experiments showed a marked downregulation of neurofibromin expression in the dentate gyrus of both naive and MWM-treated En2(-/-) mice. ERK phosphorylation, known to be induced in the presence of neurofibromin deficiency, was increased in the dentate gyrus of En2(-/-) mice after MWM. Treatment of En2(-/-) mice with lovastatin, an indirect inhibitor of ERK phosphorylation, markedly reduced ERK phosphorylation in the dentate gyrus, but was unable to rescue learning deficits in MWM-trained mutant mice. Further investigation is needed to unravel the complex molecular mechanisms linking dysregulation of neurofibromin-dependent pathways to spatial learning deficits in the En2 mouse model of ASD.

PMID: 25274808 [PubMed - indexed for MEDLINE]

Shining a light on CNTNAP2: complex functions to complex disorders.

January 21, 2015 - 6:29am
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Shining a light on CNTNAP2: complex functions to complex disorders.

Eur J Hum Genet. 2014 Feb;22(2):171-8

Authors: Rodenas-Cuadrado P, Ho J, Vernes SC

Abstract
The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions.

PMID: 23714751 [PubMed - indexed for MEDLINE]

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