The social brain network and autism.
Ann Neurosci. 2014 Apr;21(2):69-73
Authors: Misra V
Available research data in Autism suggests the role of a network of brain areas, often known as the 'social brain'. Recent studies highlight the role of genetic mutations as underlying patho-mechanism in Autism. This mini review, discusses the basic concepts behind social brain networks, theory of mind and genetic factors associated with Autism. It critically evaluates and explores the relationship between the behavioral outcomes and genetic factors providing a conceptual framework for understanding of autism.
PMID: 25206065 [PubMed]
A CGG-Repeat Expansion Mutation in ZNF713 Causes FRA7A: Association with Autistic Spectrum Disorder in two Families.
A CGG-Repeat Expansion Mutation in ZNF713 Causes FRA7A: Association with Autistic Spectrum Disorder in two Families.
Hum Mutat. 2014 Sep 4;
Authors: Metsu S, Rainger JK, Debacker K, Bernhard B, Rooms L, Grafodatskaya D, Weksberg R, Fombonne E, Taylor MS, Scherer SW, Kooy RF, FitzPatrick DR
We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation (∼450 repeats) in a 5' intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated pre-mutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (5-22 repeats). In a second unrelated family three siblings with ASD and their unaffected father were found to carry FRA7A pre-mutations, which were partially or mosaically methylated. In one of the affected siblings mitotic instability of the pre-mutation was observed. ZNF713 expression in LCLs in this family was increased in 3 of these 4 premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed. This article is protected by copyright. All rights reserved.
PMID: 25196122 [PubMed - as supplied by publisher]
[Participation of mTOR signal system in autistic behavior of mice modeling tuberous sclerosis].
Nihon Shinkei Seishin Yakurigaku Zasshi. 2014 Apr;34(2):51-2
Authors: Sato A, Kasai S, Kobayashi T, Takamatsu Y, Hino O, Ikeda K, Mizuguchi M
PMID: 25141393 [PubMed - indexed for MEDLINE]
Association of autism with induced or augmented childbirth.
Am J Obstet Gynecol. 2014 May;210(5):492-3
Authors: Miranda ML, Anthopolos R, Gregory SG
PMID: 24380745 [PubMed - indexed for MEDLINE]
Changes in the GRIP 1&2 scaffolding proteins in the cerebellum of the ataxic stargazer mouse.
Brain Res. 2014 Feb 10;1546:53-62
Authors: Trotman M, Barad Z, Guévremont D, Williams J, Leitch B
Glutamate receptor-interacting proteins (GRIP1&2) and protein-interacting with C kinase-1 (PICK1) are synaptic scaffold proteins associated with the stabilization and recycling of synaptic GluA2-, 3- and 4c-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). PICK1-mediated phosphorylation of GluA serine880 uncouples GRIP1&2 leading to AMPAR endocytosis, important in mediating forms of synaptic plasticity underlying learning and memory. Ataxic and epileptic stargazer mice possess a mutation in the CACNG2 gene encoding the transmembrane AMPAR-regulatory protein (TARP)-γ2 (stargazin). TARPs are AMPAR-auxiliary subunits required for efficient AMPAR trafficking to synapses. Stargazin is abundantly expressed in the cerebellum and its loss results in severe deficits in AMPAR trafficking to cerebellar synapses, particularly at granule cell (GC) synapses, leading to the ataxic phenotype of stargazers. However, how the stargazin mutation impacts on the expression of other AMPAR-interacting scaffold proteins is unknown. This study shows a significant increase in GRIP1&2, but not PICK1, levels in whole tissue and synapse-enriched extracts from stargazer cerebella. Post-embedding immunogold-cytochemistry electron microscopy showed GRIP1&2 levels were unchanged at mossy fiber-GC synapses in stargazers, which are silent due to virtual total absence of synaptic and extrasynaptic GluA2/3-AMPARs. These results indicate that loss of synaptic AMPARs at this excitatory synapse does not affect GRIP1&2 expression within the postsynaptic region of mossy fiber-GC synapses. Interestingly, increased GRIP and reduced GluA2-AMPARexpression also occur in cerebella of autistic patients. Further research establishing the role of elevated cerebellar GRIP1&2 in stargazers may help identify common cellular mechanisms in the comorbid disorders ataxia, epilepsy and autism leading to more effective treatment strategies.
PMID: 24380676 [PubMed - indexed for MEDLINE]
Mitochondrial dysfunction in autism.
Semin Pediatr Neurol. 2013 Sep;20(3):163-75
Authors: Legido A, Jethva R, Goldenthal MJ
Using data of the current prevalence of autism as 200:10,000 and a 1:2000 incidence of definite mitochondrial (mt) disease, if there was no linkage of autism spectrum disorder (ASD) and mt disease, it would be expected that 1 in 110 subjects with mt disease would have ASD and 1 in 2000 individuals with ASD would have mt disease. The co-occurrence of autism and mt disease is much higher than these figures, suggesting a possible pathogenetic relationship. Such hypothesis was initially suggested by the presence of biochemical markers of abnormal mt metabolic function in patients with ASD, including elevation of lactate, pyruvate, or alanine levels in blood, cerebrospinal fluid, or brain; carnitine level in plasma; and level of organic acids in urine, and by demonstrating impaired mt fatty acid β-oxidation. More recently, mtDNA genetic mutations or deletions or mutations of nuclear genes regulating mt function have been associated with ASD in patients or in neuropathologic studies on the brains of patients with autism. In addition, the presence of dysfunction of the complexes of the mt respiratory chain or electron transport chain, indicating abnormal oxidative phosphorylation, has been reported in patients with ASD and in the autopsy samples of brains. Possible pathogenetic mechanisms linking mt dysfunction and ASD include mt activation of the immune system, abnormal mt Ca(2+) handling, and mt-induced oxidative stress. Genetic and epigenetic regulation of brain development may also be disrupted by mt dysfunction, including mt-induced oxidative stress. The role of the purinergic system linking mt dysfunction and ASD is currently under investigation. In summary, there is genetic and biochemical evidence for a mitochondria (mt) role in the pathogenesis of ASD in a subset of children. To determine the prevalence and type of genetic and biochemical mt defects in ASD, there is a need for further research using the latest genetic technology such as next-generation sequencing, microarrays, bioinformatics, and biochemical assays. Because of the availability of potential therapeutic options for mt disease, successful research results could translate into better treatment and outcome for patients with mt-associated ASD. This requires a high index of suspicion of mt disease in children with autism who are diagnosed early.
PMID: 24331358 [PubMed - indexed for MEDLINE]
Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming.
Proc Natl Acad Sci U S A. 2014 Sep 5;
Authors: Picard M, Zhang J, Hancock S, Derbeneva O, Golhar R, Golik P, O'Hearn S, Levy S, Potluri P, Lvova M, Davila A, Lin CS, Perin JC, Rappaport EF, Hakonarson H, Trounce IA, Procaccio V, Wallace DC
Variation in the intracellular percentage of normal and mutant mitochondrial DNAs (mtDNA) (heteroplasmy) can be associated with phenotypic heterogeneity in mtDNA diseases. Individuals that inherit the common disease-causing mtDNA tRNA(Leu(UUR)) 3243A>G mutation and harbor ∼10-30% 3243G mutant mtDNAs manifest diabetes and occasionally autism; individuals with ∼50-90% mutant mtDNAs manifest encephalomyopathies; and individuals with ∼90-100% mutant mtDNAs face perinatal lethality. To determine the basis of these abrupt phenotypic changes, we generated somatic cell cybrids harboring increasing levels of the 3243G mutant and analyzed the associated cellular phenotypes and nuclear DNA (nDNA) and mtDNA transcriptional profiles by RNA sequencing. Small increases in mutant mtDNAs caused relatively modest defects in oxidative capacity but resulted in sharp transitions in cellular phenotype and gene expression. Cybrids harboring 20-30% 3243G mtDNAs had reduced mtDNA mRNA levels, rounded mitochondria, and small cell size. Cybrids with 50-90% 3243G mtDNAs manifest induction of glycolytic genes, mitochondrial elongation, increased mtDNA mRNA levels, and alterations in expression of signal transduction, epigenomic regulatory, and neurodegenerative disease-associated genes. Finally, cybrids with 100% 3243G experienced reduced mtDNA transcripts, rounded mitochondria, and concomitant changes in nuclear gene expression. Thus, striking phase changes occurred in nDNA and mtDNA gene expression in response to the modest changes of the mtDNA 3243G mutant levels. Hence, a major factor in the phenotypic variation in heteroplasmic mtDNA mutations is the limited number of states that the nucleus can acquire in response to progressive changes in mitochondrial retrograde signaling.
PMID: 25192935 [PubMed - as supplied by publisher]
Autism and Fragile X Syndrome.
Semin Neurol. 2014 Jul;34(3):258-265
Authors: Yu TW, Berry-Kravis E
Autistic spectrum disorders (ASDs) are characterized by impairments in language, social skills, and repetitive behaviors, often accompanied by intellectual disability. Advances in the genetics of ASDs are providing new glimpses into the underlying neurobiological mechanisms disrupted in these conditions. These glimpses on one hand reinforce the idea that synapse development and plasticity are one of the major pathways disrupted in autism, but beyond that are providing fresh molecular support to the idea of mechanistic parallels between idiopathic ASD and specific syndromic neurodevelopmental disorders like fragile X syndrome (FXS). Fragile X syndrome is already recognized as the most common identifiable genetic cause of intellectual disability and ASDs, with many overlapping phenotypic features. Fragile X syndrome is associated with a variety of cognitive, behavioral, physical, and medical problems, which are managed through supportive treatment. Recent major advances in the understanding of the underlying neurobiology in FXS have led to the discovery of agents that rescue phenotypes in the FXS mouse model, and early clinical trials of targeted treatments in humans with FXS. Thus translational strategies in FXS may be poised to serve as models for ASD and other cognitive disorders.
PMID: 25192504 [PubMed - as supplied by publisher]
How to use… microarray comparative genomic hybridisation to investigate developmental disorders.
Arch Dis Child Educ Pract Ed. 2014 Sep 4;
Authors: Kharbanda M, Tolmie J, Joss S
Array-comparative genomic hybridisation (array-CGH) is a relatively new test that permits close scrutiny of chromosomal structure to detect genomic microdeletions and microduplications that are invisible in a conventional karyotype. Array-CGH is now the 'first-line' genetic test in the investigation of early developmental impairments and learning difficulties, especially if the clinical picture includes dysmorphism, abnormal growth, congenital anomalies, epilepsy and autism, alone or in combination. However, due to the array-CGH report's technical content and the uncertain clinical significance of many genomic findings, the results of array-CGH studies need careful interpretation. Array-CGH trebles the frequency of diagnosis compared with conventional karyotyping, but collaborative working, involving paediatricians, clinical geneticists and clinical scientists, is most important for interpretation of the results of new genomic investigations in everyday clinical practice.
PMID: 25189327 [PubMed - as supplied by publisher]
[Mutational analysis of the methyl-CpG-binding protein 2 (MECP2) gene in male autism patients].
Beijing Da Xue Xue Bao. 2013 Apr 18;45(2):197-201
Authors: Wang SM, Li M, Yang YL, Pan H, Liu J, Pan KF, Bu DF
OBJECTIVE: To investigate mutations in the methyl-CpG-binding protein 2 (MECP2) gene in male autism patients by PCR, denaturing high-performance liquid chromatography (DHPLC) and sequencing to explore the role of mutations in MECP2 in autism patients.
METHODS: We recruited DNA samples from 44 male autism patients who matched the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DMS-IV) standards. DHPLC was used to screen the mutations in MECP2 gene, and DNA sequencing was performed for the samples with positive DHPLC results. The family members were further investigated in the patients with missense mutations in MECP2 gene.
RESULTS: Four cases were found to have mutations in MECP2 gene, including missense mutations of c.590C>T(T197M)in one case and c.602C>T(A201V)in one case, and synonymous mutations of c.1053C>G in one case and c.897C>T in one case. In addition, we found C>T variation in intron 3 at the +74 bp before exon 4, a SNP (rs2071569) usually detected in Chinese population. In the case with c.602C>T(A201V)mutation, his mother and maternal grandfather had the same mutation. His mother had normal phenotype, but his maternal grandfather had depressive disease.
CONCLUSION: Mutations in MECP2 are present in male autism patients with relatively higher prevalence, suggesting that these mutations may play roles in the pathogenesis of autism.
PMID: 23591336 [PubMed - indexed for MEDLINE]
A de novo Microdeletion of ANKRD11 Gene in a Korean Patient with KBG Syndrome.
Ann Lab Med. 2014 Sep;34(5):390-4
Authors: Lim JH, Seo EJ, Kim YM, Cho HJ, Lee JO, Cheon CK, Yoo HW
KBG syndrome is a very rare genetic disorder characterized by macrodontia of upper central incisors, global developmental delay, distinctive craniofacial features, short stature, and skeletal anomalies. Ankyrin repeat domain 11 gene (ANKRD11) has recently been identified as a causal factor of this syndrome. We describe a 6-yr-old Korean boy with features of KBG syndrome. The patient had a short stature, macrodontia, dysmorphic facial features, speech and motor delay with intellectual disability, and partial seizures as indicated by the electroencephalogram, but he was neither autistic nor had autism spectrum disorders. Using high-resolution oligonucleotide array comparative genomic hybridization, we identified a heterozygous 240-kb deletion at 16q24.3 corresponding to ANKRD11. This patient provided additional evidence on the influence of ANKRD11 in KBG syndrome and suggested that deletion limited to ANKRD11 is unlikely to cause autism.
PMID: 25187894 [PubMed - in process]
The Diverse Genetic Landscape of Neurodevelopmental Disorders.
Annu Rev Genomics Hum Genet. 2014 Aug 31;15:195-213
Authors: Hu WF, Chahrour MH, Walsh CA
Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.
PMID: 25184530 [PubMed - as supplied by publisher]
Introduction: Shankopathies and related autism spectrum disorders.
Dev Neurobiol. 2014 Feb;74(2):83-4
PMID: 24343904 [PubMed - indexed for MEDLINE]
Duplication of the 15q11-q13 region: clinical and genetic study of 30 new cases.
Eur J Med Genet. 2014 Jan;57(1):5-14
Authors: Al Ageeli E, Drunat S, Delanoë C, Perrin L, Baumann C, Capri Y, Fabre-Teste J, Aboura A, Dupont C, Auvin S, El Khattabi L, Chantereau D, Moncla A, Tabet AC, Verloes A
BACKGROUND: 15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1-BP5). Duplication of this region is observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism.
METHODS: Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region.
RESULTS: Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader-Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1-BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3, MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.
PMID: 24239951 [PubMed - indexed for MEDLINE]
A blueprint for research on Shankopathies: a view from research on autism spectrum disorder.
Dev Neurobiol. 2014 Feb;74(2):85-112
Authors: Carbonetto S
Autism spectrum disorders (ASD) are associated with mutations in a host of genes including a number that function in synaptic transmission. Phelan McDermid syndrome involves mutations in SHANK3 which encodes a protein that forms a scaffold for glutamate receptors at the synapse. SHANK3 is one of the genes that underpins the synaptic hypothesis for ASD. We discuss this hypothesis with a view to the broader context of ASD and with special emphasis on highly penetrant genetic disorders including Shankopathies. We propose a blueprint for near and longer-term goals for fundamental and translational research on Shankopathies.
PMID: 24218108 [PubMed - indexed for MEDLINE]
The emerging role of SHANK genes in neuropsychiatric disorders.
Dev Neurobiol. 2014 Feb;74(2):113-22
Authors: Guilmatre A, Huguet G, Delorme R, Bourgeron T
The genetic heterogeneity of neuropsychiatric disorders is high, but some pathways emerged, notably synaptic functioning. A large number of mutations have been described in genes such as neuroligins, neurexins, and SHANK that play a role in the formation and the maintenance of synapses. This review focuses on the disorders associated with mutations in SHANK3 and the other members of its family, SHANK1 and SHANK2. SHANKs are scaffolding proteins of the postsynaptic density of glutamatergic synapses. SHANK3 has been described in the Phelan-McDermid syndrome (PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to moderate to severe intellectual disability (ID) and poor language. The evolution of patients with PMS includes symptoms of bipolar disorder and regression. SHANK2 has been identified in patients with ASD with mild to severe ID. SHANK1 has been associated with high-functioning autism in male patients, while carrier females only display anxiety and shyness. Finally, based on neuropathological findings in animal models and patients, a possible role of SHANK in Alzheimer's disease is discussed. Altogether, this review describes the clinical trajectories associated with different mutations of the SHANK genes and provides information to further investigate the role of the SHANK genes in neuropsychiatric disorders.
PMID: 24124131 [PubMed - indexed for MEDLINE]
Increasing our understanding of human cognition through the study of Fragile X Syndrome.
Dev Neurobiol. 2014 Feb;74(2):147-77
Authors: Cook D, Nuro E, Murai KK
Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior.
PMID: 23723176 [PubMed - indexed for MEDLINE]
Molecular basis for prospective pharmacological treatment strategies in intellectual disability syndromes.
Molecular basis for prospective pharmacological treatment strategies in intellectual disability syndromes.
Dev Neurobiol. 2014 Feb;74(2):197-206
Authors: Verpelli C, Galimberti I, Gomez-Mancilla B, Sala C
A number of mutated genes that code for proteins concerned with brain synapse function and circuit formation have been identified in patients affected by intellectual disability (ID) syndromes over the past 15 years. These genes are involved in synapse formation and plasticity, the regulation of dendritic spine morphology, the regulation of the synaptic cytoskeleton, the synthesis and degradation of specific synapse proteins, and the control of correct balance between excitatory and inhibitory synapses. In most of the cases, even mild alterations in synapse morphology, function, and balance give rise to mild or severe IDs. These studies provided a rationale for the development of pharmacological agents that are able to counteract functional synaptic anomalies and potentially improve the symptoms of some of these conditions. This review summarizes recent findings on the functions of some of the genes responsible for ID syndromes and some of the new potential pharmacological treatments for these diseases.
PMID: 23695997 [PubMed - indexed for MEDLINE]
A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders.
Dev Neurobiol. 2014 Feb;74(2):136-46
Authors: Grabrucker AM
The establishment and maintenance of synaptic contacts as well as synaptic plasticity are crucial factors for normal brain function. The functional properties of a synapse are largely dependent on the molecular setup of synaptic proteins. Multidomain proteins of the ProSAP/Shank family act as major organizing scaffolding elements of the postsynaptic density (PSD). Interestingly, ProSAP/Shank proteins at glutamatergic synapses have been linked to a variety of Autism Spectrum Disorders (ASDs) including Phelan McDermid Syndrome, and deregulation of ProSAP/Shank has been reported in Alzheimer's disease. Although the precise molecular mechanism of the dysfunction of these proteins remains unclear, an emerging model is that mutations or deletions impair neuronal circuitry by disrupting the formation, plasticity and maturation of glutamatergic synapses. Several PSD proteins associated with ASDs are part of a complex centered around ProSAP/Shank proteins and many ProSAP/Shank interaction partners play a role in signaling within dendritic spines. Interfering with any one of the members of this signaling complex might change the output and drive the system towards synaptic dysfunction. Based on recent data, it is possible that the concerted action of ProSAP/Shank and Zn(2+) is essential for the structural integrity of the PSD. This interplay might regulate postsynaptic receptor composition, but also transsynaptic signaling. It might be possible that environmental factors like nutritional Zn(2+) status or metal ion homeostasis in general intersect with this distinct pathway centered around ProSAP/Shank proteins and the deregulation of any of these two factors may lead to ASDs.
PMID: 23650259 [PubMed - indexed for MEDLINE]
Therapeutic approaches for shankopathies.
Dev Neurobiol. 2014 Feb;74(2):123-35
Authors: Wang X, Bey AL, Chung L, Krystal AD, Jiang YH
Despite recent advances in understanding the molecular mechanisms of autism spectrum disorders (ASD), the current treatments for these disorders are mostly focused on behavioral and educational approaches. The considerable clinical and molecular heterogeneity of ASD present a significant challenge to the development of an effective treatment targeting underlying molecular defects. Deficiency of SHANK family genes causing ASD represent an exciting opportunity for developing molecular therapies because of strong genetic evidence for SHANK as causative genes in ASD and the availability of a panel of Shank mutant mouse models. In this article, we review the literature suggesting the potential for developing therapies based on molecular characteristics and discuss several exciting themes that are emerging from studying Shank mutant mice at the molecular level and in terms of synaptic function.
PMID: 23536326 [PubMed - indexed for MEDLINE]