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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autism is a particularly complex disorder when considered from virtually any methodological framework, including the perspective of human genetics. We first present a review of the genetic analysis principles relevant for discussing autism genetics research. From this body of work we highlight results from three candidate genes, REELIN (RELN), SEROTONIN TRANSPORTER (5HTT), and ENGRAILED 2 (EN2) and discuss the relevant neuroscience, molecular genetics, and statistical results that suggest involvement of these genes in autism susceptibility. As will be shown, the statistical results from genetic analysis, when considered alone, are in apparent conflict across research groups. We use these three candidate genes to illustrate different problems in synthesizing results from non-overlapping research groups examining the same problem. However, when basic genetic principles and results from other scientific disciplines are incorporated into a unified theoretical framework, at least some of the difficulties with interpreting results can be understood and potentially overcome as more data becomes available to the field of autism research. Integrating results from several scientific frameworks provides new hypotheses and alternative data collection strategies for future work.
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PMID:Three autism candidate genes: a synthesis of human genetic analysis with other disciplines. 1574 47

Our previous research involving 167 nuclear families from the Autism Genetic Resource Exchange (AGRE) demonstrated that two intronic SNPs, rs1861972 and rs1861973, in the homeodomain transcription factor gene ENGRAILED 2 (EN2) are significantly associated with autism spectrum disorder (ASD). In this study, significant replication of association for rs1861972 and rs1861973 is reported for two additional data sets: an independent set of 222 AGRE families (rs1861972-rs1861973 haplotype, P=.0016) and a separate sample of 129 National Institutes of Mental Health families (rs1861972-rs1861973 haplotype, P=.0431). Association analysis of the haplotype in the combined sample of both AGRE data sets (389 families) produced a P value of .0000033, whereas combining all three data sets (518 families) produced a P value of .00000035. Population-attributable risk calculations for the associated haplotype, performed using the entire sample of 518 families, determined that the risk allele contributes to as many as 40% of ASD cases in the general population. Linkage disequilibrium (LD) mapping with the use of polymorphisms distributed throughout the gene has shown that only intronic SNPs are in strong LD with rs1861972 and rs1861973. Resequencing and association analysis of all intronic SNPs have identified alleles associated with ASD, which makes them candidates for future functional analysis. Finally, to begin defining the function of EN2 during development, mouse En2 was ectopically expressed in cortical precursors. Fewer En2-transfected cells than controls displayed a differentiated phenotype. Together, these data provide further genetic evidence that EN2 might act as an ASD susceptibility locus, and they suggest that a risk allele that perturbs the spatial/temporal expression of EN2 could significantly alter normal brain development.
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PMID:Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus. 1625 43

Autism spectrum disorder (ASD) is a prevalent and inheritable neurodevelopmental disorder. Recent human genetic studies are consistent with the homeobox transcription factor, ENGRAILED 2 (EN2), being an ASD susceptibility gene. En2 knockout mice (En2(-/-)) display subtle cerebellar neuropathological changes similar to what has been observed in the ASD brain. To investigate whether En2(-/-) mice displayed abnormal behavior relevant to ASD, they were monitored in tasks designed to assess social maturation as well as learning and memory. Deficits in social behavior were detected in En2(-/-) mice across maturation that included decreased play, reduced social sniffing and allogrooming, and less aggressive behavior. Deficits in two spatial learning and memory tasks were also observed. Because locomotor activity was a component of many of the behavioral tasks, this was measured at various stages of development. Locomotor activity was not compromised in the knockout. However, a more thorough analysis of motor behavior in En2(-/-) mice revealed deficits in specific motor tasks. To determine whether neurochemical changes were associated with these behavioral phenotypes, monoamine levels in specific brain regions were assessed. A cerebellar-specific increase in serotonin and its metabolite was observed. Interestingly, several reports have suggested that the serotonin pathway is affected in ASD. We conclude that En2(-/-) mice display behavioral and neurochemical changes, in addition to genetic and neuropathological changes, relevant to ASD. Therefore, these mice may be useful as an animal model of autism.
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PMID:En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder. 1693 68

Human ENGRAILED 2 (EN2) gene is localized to 7q36, an autism susceptibility locus. En2 knockout mice display hypoplasia of cerebellum and a decrease in the number of Purkinje cell, which are similar to those reported for individuals with autism. Furthermore, deficits in social behavior were detected in En2(-/-) mice. Two recent studies have demonstrated that two intronic SNPs (rs1861972, rs1861973) in the EN2 gene are significantly associated with autism. To investigate whether this finding could be replicated in Chinese Han population, we performed the association study between eight single nucleotide polymorphisms (SNPs) of the EN2 gene and autism in 210 Chinese Han trios, using the family-based association test (FBAT). The present study demonstrated that a preferential transmission of the rs3824068 A-allele to affected offspring (A > G: Z = 2.399, P = 0.0165). After the Bonferroni correction, this statistical significance of preferential transmission did not remain. However, when haplotypes were constructed with multiple markers, a number of haplotypes including three two-marker haplotypes, nine three-marker haplotypes, one four-marker haplotype, and one six-marker haplotype, all of which contain the major allele A of rs3824068, displayed significantly associated with autism. These results were still significant after using the permutation method to obtain empirical P values. Thus, our data provide evidence that the EN2 gene may be implicated in the predisposition to autism in the Chinese Han population.
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PMID:Association of the ENGRAILED 2 (EN2) gene with autism in Chinese Han population. 1794 1

Homeobox protein engrailed-2 (EN-2), is a subtype of the homeoprotein transcription factors of EN family. It can be transported between cells in culture by unconventional secretion and internalization mechanisms. When internalized, it can activate the transcription or translation. EN-2 had been considered to be an important transcriptional factor during the embryonic development , it involved in the regulation of anteroposterior polarity. In recent years, much more functions of EN-2 are revealed. It controls synaptic choice as well as axon projections; and there are some relationships between EN-2 and Parkinson's disease. Furthermore, EN-2 is thought to be a candidate oncogene in human breast cancer and a candidate gene of Autism Spectrum Disorder. The structure, distribution, function and regulation of EN-2 as well as the relationships between EN-2 and some diseases are reviewed in the present article.
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PMID:[EN-2: a multi-functional transcription factor of vertebrates]. 1866 77

ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders.
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PMID:Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice. 2282 97