Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Taxonomic features of fragile X syndrome (FXS) associated with the fragile X mutation have evolved over several decades. Males are more severely impacted cognitively than females, but both show declines in IQ scores as they age. Although many males with FXS exhibit autistic-like features, autism does not occur more frequently in males with FXS than among males with mental retardation (MR). FXS is caused by inactivation of the FMR1 gene located on Xq27.3. FMRP, the protein produced by FMR1, has been detected in most organs and in brain. In cells, it is located primarily in cytoplasm and contains motifs found in RNA-binding proteins. The FMRP N-terminal contains a functional nuclear localization signal which permits the protein to shuttle between cytoplasm and nucleus. FMR1 knockout mice show subtle behavioral and visual-spatial difficulties. Analysis of their brain tissue suggests absence of FMRP impairs synaptic maturation. Individuals with the fragile premutation produce FMRP, and the phenotype associated with the premutation has been controversial. However, there seems to be a higher incidence of premature ovarian failure in women with the premutation than is found in the general female population. This may be related to unusual increases in mRNA levels in premutation carriers.
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PMID:FMR1 gene and fragile X syndrome. 1118 Feb 23

Recent advances in our understanding of the clinical and molecular features of the fragile-X mental-retardation 1 gene, FMR1, highlight the importance of single-gene disorders. 15 years after its discovery, FMR1 continues to reveal new and unexpected clinical presentations and molecular mechanisms. Loss of function of FMR1 is a model for neurodevelopmental and behavioural disorders, including mental retardation, autism, anxiety, and mood instability. In addition, overexpression and CNS toxicity of FMR1 mRNA causes a late-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). A similar mechanism is probably involved in premature ovarian failure, which affects up to 20% of female carriers of an altered FMR1 gene.
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PMID:Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. 1716 1

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are associated with autism spectrum disorder in childhood, premature ovarian failure, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS, and perhaps the other clinical presentations among carriers, are thought to be due to toxic gain-of-function of elevated levels of the expanded-repeat FMR1 mRNA. Previous structural MRI studies have implicated the amygdala as a potential site of dysfunction underlying social deficits and/or risk for FXTAS. As a preliminary investigation of this possible association, adult males with the premutation, and male controls matched for IQ, age and education, completed three protocols that probe amygdala and sympathetic function: (i) a functional MRI paradigm that measures brain response to fearful faces; (ii) a fear-potentiated startle paradigm that differentiates responses to fearful faces and fearful non-social images and (iii) measurement of skin conductance level during a brief social encounter. Compared with controls, men with the FMR1 premutation demonstrated diminished brain activation in the amygdala and several brain areas that mediate social cognition while viewing fearful faces. The reduced amygdala activation in the premutation group was significantly associated with self-report of psychological symptoms on the Symptom Checklist-90--Revised. These men also displayed a lack of startle potentiation while viewing fearful faces and showed reduced skin conductance response when greeting an unfamiliar experimenter in comparison with the control group. The current findings may be related to social cognition deficits reported previously in children and adults with the premutation. The aetiology for this dysfunction may be elevated FMR1 mRNA or reduced FMR1 protein that occurs in carriers with higher premutation CGG repeat alleles.
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PMID:Amygdala dysfunction in men with the fragile X premutation. 1716 60

Fragile X syndrome, the most common inherited cause of intellectual impairment and the most common single gene associated with autism, generally occurs for fragile X mental retardation 1 (FMR1) alleles that exceed 200 CGG repeats (full-mutation range). Currently, there are no unbiased estimates of the number of full-mutation FMR1 alleles in the general population; a major obstacle is the lack of an effective screening tool for expanded FMR1 alleles in large populations. We have developed a rapid polymerase chain reaction (PCR)-based screening tool for expanded FMR1 alleles. The method utilizes a chimeric PCR primer that targets randomly within the expanded CGG region, such that the presence of a broad distribution of PCR products represents a positive result for an expanded allele. The method is applicable for screening both males and females and for allele sizes throughout the premutation (55 to 200 CGG repeats) and full-mutation ranges. Furthermore, the method is capable of rapid detection of expanded alleles using as little as 1% of the DNA from a single dried blood spot. The methodology presented in this work is suitable for screening large populations of newborn or those at high risk (eg, autism, premature ovarian failure, ataxia, dementia) for expanded FMR1 alleles. The test described herein costs less than $5 per sample for materials; with suitable scale-up and automation, the cost should approach $1 per sample.
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PMID:A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. 1816 73

An interstitial deletion of about 12Mb at 7q33-q36 was found in an adult female affected by autism and primary amenorrhea. Two genes, CNTNAP2 and NOBOX, both contained within the deletion region, have been recently associated with autism susceptibility and premature ovarian failure, respectively. Our findings reinforce the hypothesis that haploinsufficiency of both these genes is sufficient for autism development and occurrence of primary amenorrhea, confirming a previous case in which CNTNAP2 had been disrupted by a chromosome inversion and possibly enlarging the phenotype of ovarian function disturbances already demonstrated for NOBOX mutations.
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PMID:A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea. 1867 47

We describe a girl with mild facial anomalies, mild mental retardation, and atypical autism with a remarkable behavioral phenotype of persistent anger, aggression, and dysphoria. The occurrence of late-onset tremor and premature ovarian failure in the maternal branch of the family pointed to a possible defect in the FMR1 gene. Indeed, the patient carried a full FMR1 mutation. Unexpectedly, both alleles of the gene were almost completely methylated. Cytogenetic examination of the patient revealed in addition a large de novo deletion in band Xp22 on one of her X chromosomes. The deletion was fine mapped using oligonucleotide array CGH, and its breakpoints were localized using sequencing. The size of the deletion was about 17.4 Mb, and it contained more than 90 protein-coding genes. Microsatellite analysis indicated paternal origin of the aberrant chromosome. The large rearrangement was the most probable cause of the X-inactivation skewing, thus explaining the methylation of not only the expanded (maternal) but also the normal (paternal) FMR1 alleles. This pattern of skewed X-inactivation was confirmed using the analysis of methylation at the AR locus. The relatively mild phenotype of the patient resulted most likely from unmasking of the FMR1 defect. Although the deleted region contained many important genes, the phenotypic contribution of the rearranged X chromosome was probably limited by its almost complete inactivation. However, reduced dose of several genes escaping X-inactivation might also play a role in the phenotype of the patient.
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PMID:FMR1 gene expansion, large deletion of Xp, and skewed X-inactivation in a girl with mental retardation and autism. 2042 35

The L10 ribosomal protein (RPL10) plays a role in the binding of the 60 S and 40 S ribosomal subunits and in mRNA translation. The evidence indicates that RPL10 also has multiple extra-ribosomal functions, including tumor suppression. Recently, the presence of RPL10 in prostate and ovarian cancers was evaluated, and it was demonstrated to be associated with autistic disorders and premature ovarian failure. In the present work, we successfully cloned and expressed full-length human RPL10 (hRPL10) protein and isolated inclusion bodies containing this protein that had formed under mild growth conditions. The culture produced 376mg of hRPL10 protein per liter of induced bacterial culture, of which 102.4mg was present in the soluble fraction, and 25.6mg was recovered at approximately 94% purity. These results were obtained using a two-step process of non-denaturing protein extraction from pelleted inclusion bodies. We studied the characteristics of this protein using circular dichroism spectroscopy and by monitoring the changes induced by the presence or absence of zinc ions using fluorescence spectrometry. The results demonstrated that the protein obtained using these non-conventional methods retained its secondary and tertiary structure. The conformational changes induced by the incorporation of zinc suggested that this protein could interact with Jun or the SH3 domain of c-yes. The results suggested that the strategy used to obtain hRPL10 is simple and could be applied to obtaining other proteins that are susceptible to degradation.
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PMID:A simple strategy for the purification of native recombinant full-length human RPL10 protein from inclusion bodies. 2496 37