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)

Syndromes of disordered 'chromatin remodeling' are unique in medicine because they arise from a general deregulation of DNA transcription caused by mutations in genes encoding enzymes which mediate changes in chromatin structure. Chromatin is the packaged form of DNA in the eukaryotic cell. It consists almost entirely of repeating units, called nucleosomes, in which short segments of DNA are wrapped tightly around a disk-like structure comprising two subunits of each of the histone proteins H2A, H2B, H3 and H4. Histone proteins are covalently modified by a number of different adducts (i.e. acetylation and phosphorylation) that regulate the tightness of the DNA-histone interactions. Mutations in genes encoding enzymes that mediate chromatin structure can result in a loss of proper regulation of chromatin structure, which in turn can result in deregulation of gene transcription and inappropriate protein expression. In this review we present examples of representative genetic diseases that arise as a consequence of disordered chromatin remodeling. These include: alpha-thalassemia/mental retardation syndrome, X-linked (ATR-X); Rett syndrome (RS); immunodeficiency-centromeric instability-facial anomalies syndrome (ICF); Rubinstein-Taybi syndrome (RSTS); and Coffin-Lowry syndrome (CLS).
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PMID:Syndromes of disordered chromatin remodeling. 1285 1

Rett syndrome (RTT) is one of the most common neurodevelopmental disorders in females. The disease is caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2), and various mutations have been reported. The phenotypic spectrum in both female and male patients is diverse, ranging from very mild to congenital encephalopathy and prenatal lethality. In this study, the question was addressed as to whether implementation of systematic screening of MECP2 in patients with an unexplained mental retardation in DNA diagnostics would be reasonable, and the spectrum of phenotypes resulting from mutations in this gene was further explored. Mutational analysis of MECP2 was performed in mentally retarded female patients who were negative for FMR1 CGG repeat expansion, in male and female patients with clinical features suggestive of either Angelman or Prader-Willi syndrome without methylation defects on chromosome 15q11-q13. In the cohort of females negative for the molecular Fragile-X studies (N=92), one nonsense mutation (p.Q406X) was found. In the cohort of Angelman-negative patients (N=63), two missense mutations (p.R133C in a female patient and a mosaic p.T158M in a male patient) were found, which have been reported many times in patients with classical RTT syndrome. In the Prader-Willi-negative group (N=98), no pathogenic mutations were found. The results support testing of patients with features suggestive of Angelman syndrome, but without methylation defects on chromosome 15q11-q13 for mutations in MECP2. In the remaining patients with unexplained mental retardation, additional clinical features should determine whether analysis of MECP2 is indicated.
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PMID:MECP2 analysis in mentally retarded patients: implications for routine DNA diagnostics. 1456 Mar 7

Non-syndromic X-linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In Rett syndrome (RTT), an X-linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl-CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in-frame deletion DeltaP387-M466 was found in the 3' region. The patients had severe to mild non-progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non-progressive MR, poor motor co-ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. Phenotype-genotype correlation could thus be suspected and is discussed in these three families.
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PMID:MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation. 1459 36

The association of Rett syndrome with pathogenic mutations of the methyl-CpG binding protein 2 (MECP2) gene was first made in 1999. Since that time, it has been found that the clinical phenotype can, at least in part, be explained in terms of the type and location of the MECP2 mutation and epigenetic factors such as skewing of X-chromosome inactivation. In addition, MECP2 mutations may be associated with non-Rett syndrome clinical phenotypes, including nonsyndromic and syndromic X-linked mental retardation and Angelman-like phenotypes. Intense research efforts are currently focused on understanding the pathogenesis of Rett syndrome, using sophisticated techniques such as microarray analysis, and the development of mouse models, with an ultimate aim being the development of targeted therapies that could ameliorate or even prevent the devastating consequences of this enigmatic neurodevelopmental disorder.
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PMID:MECP2 and beyond: phenotype-genotype correlations in Rett syndrome. 1464 47

Girls with Rett syndrome display signs of neuronal dysfunction including mental retardation, seizures, stereotyped movements, and abnormal breathing and autonomic control. Decelerating head growth during infancy might reflect a disorder in production or pruning of neuronal synapses or both. Recent immunocytochemical studies in rodent brain investigating development of MeCP2, the transcription factor mutated in Rett syndrome, suggest that expression is delayed until the time of synapse formation. These findings are consistent with other evidence that Rett syndrome disrupts genetic programs that establish and refine synaptic connections.
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PMID:Neurobiology of Rett syndrome. 1464 50

Angelman syndrome (AS) is an imprinted neurobehavioral disorder characterized by mental retardation, absent speech, excessive laughter, seizures, ataxia, and a characteristic EEG pattern. Classical lesions, including deletion, paternal disomy, or epigenetic mutation, are confirmatory of AS diagnoses in 80% of cases. Loss-of-function mutations of the UBE3A gene have been identified in approximately 8% of AS cases, failing to account for the remaining patient population, and there appears to be a higher prevalence of mutations in familial than sporadic cases. We screened UBE3A in 45 index cases of AS without obvious 15q11-13 abnormalities. Pathological mutations were identified in 3/6 (50%) familial and 4/39 (>10%) sporadic cases. By combining our data with those of the literature, we demonstrate statistically that the frequency of UBE3A mutations is significantly higher in the familial than sporadic subsets of AS. This indicates that an independent molecular mechanism or 'phenocopy' exists for the sporadic group. Rett syndrome (RS), caused by mutations of the MECP2 gene, and patients with deletions of 22q13.3 --> qter, have overlapping clinical features with AS. We screened 24 of the sporadic AS cases without detectable UBE3A mutations for mutations of MECP2, but found none. A separate cohort of 43 atypical patients with features common to AS and RS, in whom 15q11-13 lesions and 22q13.3 --> qter deletion had been ruled out, were also screened for MECP2 mutations. One male patient was mosaic for a frameshift mutation of this gene (previously reported). While MECP2 mutations can cause a phenotype reminiscent of AS in rare cases, they fail to account for the excess of sporadic patients with a definitive clinical diagnosis of AS.
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PMID:Investigation of UBE3A and MECP2 in Angelman syndrome (AS) and patients with features of AS. 1498 18

Stereotypic movements are repetitive patterns of movements whose physiopathology and relations to other neurobehavioural disorders are still only poorly understood. In this paper our aim is to distinguish between primary stereotypic movements, which are the sole manifestation of an anomaly, while the complementary examinations, except for those involving molecular genetics, are normal; associated stereotypic movements, when they meet primary disorder criteria but there are other coexisting independent neurological signs, that is to say, they are neither the cause nor the consequence of the movement disorder; and secondary stereotypic movements, when they are the consequence of a lesion or acquired neurological dysfunction. Examples of primary stereotypic movements include episodes of parasomnia, such as head rocking, in subjects who are otherwise normal, and stereotypic movements due to emotional disorders, severe environmental deprivation or in institutionalised infants. Examples of associated stereotypic movements are those observed in Rett syndrome, in subjects with sensory defects or with mental retardation due to a variety of causes. And as instances of secondary stereotypic movements we have those that can be seen in infinite like syndrome caused by congenital cerebellar lesions. The purpose of the classification is to lay the foundations for the identification of new syndromes, which would without a doubt facilitate research into their physiopathology, their aetiology and the possible therapeutic attitude to be adopted.
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PMID:[Primary versus secondary stereotypic movements]. 1501 Nov 49

Clinical disorders of brain plasticity are common in the practice of child neurology. Children have an enhanced capacity for brain plasticity compared to adults as demonstrated by their superior ability to learn a second language or their capacity to recover from brain injuries or radical surgery such as hemispherectomy for epilepsy. Basic mechanisms that support plasticity during development include persistence of neurogenesis in some parts of the brain, elimination of neurons through apoptosis or programmed cell death, postnatal proliferation and pruning of synapses, and activity-dependent refinement of neuronal connections. Brain plasticity in children can be divided into four types: adaptive plasticity that enhances skill development or recovery from brain injury; impaired plasticity associated with cognitive impairment; excessive plasticity leading to maladaptive brain circuits; and plasticity that becomes the brain's 'Achilles' Heel' because makes it vulnerable to injury. A broad group of pediatric neurologic disorders can be understood in terms of their impact on fundamental mechanisms for brain plasticity. These include neurofibromatosis, tuberous sclerosis, Fragile X syndrome, other inherited forms of mental retardation, cretinism, Coffin-Lowry syndrome, lead poisoning, Rett syndrome, epilepsy, hypoxic-ischemic encephalopathy and cerebral palsy.
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PMID:Clinical disorders of brain plasticity. 1503 25

MeCP2 is the founder member of a family of methyl-CpG-binding proteins able to repress transcription from methylated DNA. To date, MeCP2 action seems to involve the delivery on modified DNA of histone deacetylase activity, followed by histone methylating activity. It has been recently demonstrated that MECP2 mutations cause Rett syndrome, a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that a novel Xenopus laevis protein of 20 kDa, p20, is able to interact in vivo and in vitro with MeCP2. The p20 sequence revealed that it belongs to the family of the WAP (whey acidic protein) proteins, often functioning as a protease inhibitor. Therefore, we asked whether the p20 can influence the MeCP2 half-life. We demonstrate that, indeed, the xp20 not only can significantly increase the stability of an exogenously expressed MeCP2 in Xenopus oocytes but also can stabilize the human endogenous MeCP2. The capability of the mammalian methyl-CpG-binding protein to interact with p20 is confirmed by co-immunoprecipitation experiments performed overexpressing the WAP protein. Glutathione S-transferase pull-down assays reveal that the MeCP2 residues localized between the methyl-binding domain and the transcriptional repression domain is the primary interaction surface. Our data suggest that regulation of MeCP2 metabolism might be of relevant importance; in accordance with this, previous results have shown that some Rett syndrome mutations are characterized by a decrease in MeCP2 stability.
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PMID:A novel protein, Xenopus p20, influences the stability of MeCP2 through direct interaction. 1505 64

Rett syndrome, one of the leading causes of mental retardation and developmental regression in girls, is the first pervasive developmental disorder with a known genetic cause. The majority of cases of sporadic Rett syndrome are caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 binds methylated DNA and likely regulates gene expression and chromatin structure. Genotype/phenotype analysis revealed that the phenotypic spectrum of MECP2 mutations in humans is broader than initially suspected: Mutations have been discovered in Rett syndrome variants, mentally retarded males, and autistic children. A variety of in vivo and in vitro models has been developed that allow analysis of MeCP2 function and pathogenic studies of Rett syndrome. Because the neuropathology of Rett syndrome shares certain features with other neurodevelopmental disorders, a common pathogenic process may underlie these disorders. Thus, Rett syndrome is a prototype for the genetic, molecular, and neurobiological analysis of neurodevelopmental disorders.
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PMID:Rett syndrome: a prototypical neurodevelopmental disorder. 1507 Apr 86


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