Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity and regulates gene transcription. Here we show that Cited2-/- embryos die with cardiac malformations, adrenal agenesis, abnormal cranial ganglia and exencephaly. The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches. We find increased apoptosis in the midbrain region and a marked reduction in ErbB3-expressing neural crest cells in mid-embryogenesis. We show that CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2-/- embryonic fibroblasts and is rescued by ectopically expressed CITED2. As certain Tfap2 isoforms are essential in neural crest, neural tube and cardiac development, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.
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PMID:Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. 1169 77

A majority of the bones of the vertebrate cranial vault and craniofacial complex develop via intramembranous ossification, and are separated by fibrous sutures that undergo osteogenic differentiation in response to growth stimuli. Craniosynostosis is a common human birth defect that results from the premature bony fusion within skull sutures, and causes a myriad of complications including mental retardation and craniofacial anomalies. Synostosis of facial sutures has been reported to cause midfacial hypoplasia in some craniosynostosis cases, but most studies focus on cranial vault sutures. In this study, we have generated a mouse model of frontonasal suture synostosis and midfacial hypoplasia through the tissue-specific elimination of the AP-2alpha transcription factor. We report here the generation AP-2CRE, a frontonasal process (FNP)- and limb-specific CRE recombinase allele that is directed by human AP-2alpha promoter and enhancer elements. We used the AP-2CRE line in combination with the conditional AP-2alpha line to produce a new frontonasal knockout (FKO) mutant that lacks AP-2alpha in the FNP and limbs. FKO mice exhibit shortened snouts and wide-set eyes that become apparent at postnatal day 15. The most prominent defects in FKO snouts are (1) a lack of growth within the frontonasal sutures, and (2) a reduction in the snout vasculature. Additional defects are observed in the FKO nasal bones and sutures, the nasal cavity cartilage and bony projections, and the olfactory epithelium. The characteristics of the FKO mouse model are a unique combination of midfacial growth anomalies, and provide the first evidence that AP-2alpha is essential for appropriate postnatal craniofacial morphogenesis.
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PMID:Frontonasal process-specific disruption of AP-2alpha results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects. 1497 18

Fragile X syndrome, the most common heritable form of mental retardation, is caused by silencing of the FMR1 (fragile X mental retardation-1 gene). The protein product of this gene, FMRP (fragile X mental retardation protein), is thought to be involved in the translational regulation of mRNAs important for learning and memory. In mammals, there are two homologues of FMRP, namely FXR1P (fragile X-related protein 1) and FXR2P. Disruption of Fxr2 in mice produces learning and memory deficits, and Fmr1 and Fxr2 double-knockout mice have exaggerated impairments in certain neurobehavioral phenotypes relative to the single gene knockouts. This has led to the suggestion that FMR1 and FXR2 functionally overlap and that increasing the expression of FXR2P may ameliorate the symptoms of an FMRP deficiency. Interestingly, the region upstream of the FXR2 translation start site acts as a bidirectional promoter in rodents, driving transcription of an alternative transcript encoding the ABP (androgen-binding protein) [aABP (alternative ABP promoter)]. To understand the regulation of the human FXR2 gene, we cloned the evolutionarily conserved region upstream of the FXR2 translation start site and showed that it also has bidirectional promoter activity in both neuronal and muscle cells as evidenced by luciferase reporter assay studies. Alignment of the human, mouse, rat, rabbit and dog promoters reveals several highly conserved transcription factor-binding sites. Gel electrophoretic mobility-shift assays, chromatin immunoprecipitation studies and co-transfection experiments with plasmids expressing these transcription factors or dominant-negative versions of these factors showed that NF-YA (nuclear transcription factor Yalpha), AP2 (activator protein 2), Nrf1 (nuclear respiratory factor/alpha-Pal) and Sp1 (specificity protein 1) all bind to the FXR2 promoter both in vitro and in vivo and positively regulate the FXR2 promoter.
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PMID:NF-Y, AP2, Nrf1 and Sp1 regulate the fragile X-related gene 2 (FXR2). 1688 7