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)

Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role. In about 70% of cases, AS is caused by de novo maternal deletions at 15q11-q13 (ref. 2). Approximately 2% of AS cases are caused by paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2-3% are caused by "imprinting mutations'. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3' splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.
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PMID:UBE3A/E6-AP mutations cause Angelman syndrome. 898 71

The mucopolysaccharidoses are caused by inherited deficiencies of lysosomal enzymes involved in the degradative pathway of glycosaminoglycans. Lysosomal storage leads to cellular and organ dysfunction, including mental retardation. Storage lesions are found throughout the diseased brain, but little is known about the cellular and molecular mechanisms that underlie brain dysfunction. In the mouse model of mucopolysaccharidosis VII, we found that specific regions of the brain are vulnerable to neurodegeneration, characterized by the presence of ubiquitin inclusions, neurofilament inclusions, and reactive astrogliosis. The pathological lesions were found predominantly in the hippocampus and cerebral cortex, and they increased progressively with age. Treatment with a recombinant viral vector to correct the enzymatic defect quantitatively reversed the neurodegenerative lesions in targeted regions to normal levels.
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PMID:Selective neurodegeneration in murine mucopolysaccharidosis VII is progressive and reversible. 1244 30

Angelman syndrome is a severe neurological disorder characterized by mental retardation, absent speech, ataxia, seizures, and hyperactivity. The gene affected in this disorder is UBE3A, the gene encoding the E6-associated protein (E6AP) ubiquitin-protein ligase. Most patients have chromosomal deletions that remove the entire maternal allele of UBE3A. However, a small subset of patients have E6AP point mutations that result in single amino acid changes or short in-frame deletions that still allow translation of a full-length protein. By studying these point mutations in E6AP, we found a strong correlation between Angelman-associated mutations and a loss of E3 ubiquitin ligase activity. Interestingly the point mutations affect E6AP activity in different ways. Some mutant proteins cannot form thiol ester intermediates with ubiquitin, others retain the thiol ester formation activity but cannot efficiently transfer ubiquitin to a substrate, and still others are unstable in cells. Our results suggest that the loss of E6AP catalytic activity and likely the improper regulation of E6AP substrate(s) are important in the development of Angelman syndrome.
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PMID:Biochemical analysis of Angelman syndrome-associated mutations in the E3 ubiquitin ligase E6-associated protein. 1526 5

We have established that the gene AF4, which had long been recognized as disrupted in childhood leukemia, also plays a role in the CNS. Af4 is mutated in the robotic mouse that is characterized by ataxia and Purkinje cell loss. To determine the molecular basis of this mutation, we carried out a yeast two-hybrid screen and show that Af4 binds the E3 ubiquitin ligases Drosophila seven in absentia (sina) homologues (Siah)-1a and Siah-2 in the brain. Siah-1a and Af4 are expressed in Purkinje cells and colocalize in the nucleus of human embryonic kidney 293T and P19 cells. In vitro binding assays and coimmunoprecipitation reveal a significant reduction in affinity between Siah-1a and robotic mutant Af4 compared with wild-type, which correlates with the almost complete abolition of mutant Af4 degradation by Siah-1a. These data strongly suggest that an accumulation of mutant Af4 occurs in the robotic mouse due to a reduction in its normal turnover by the proteasome. A significant increase in the transcriptional activity of mutant Af4 relative to wild-type was obtained in mammalian cells, suggesting that the activity of Af4 is controlled through Siah-mediated degradation. Another member of the Af4 family, Fmr2, which is involved in mental handicap in humans, binds Siah proteins in a similar manner. These results provide evidence that a common regulatory mechanism exists that controls levels of the Af4/Fmr2 protein family. The robotic mouse thus provides a unique opportunity to understand how these proteins play a role in disorders as diverse as leukemia, mental retardation, and neurodegenerative disease.
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PMID:Mediation of Af4 protein function in the cerebellum by Siah proteins. 1545 19

Cri-du-chat (CDC, OMIM 123450) is a chromosomal syndrome that results from partial deletions on the short arm of chromosome 5. The clinical features of CDC normally include high-pitched cat-like cry, mental retardation, microcephaly, hypertelorism and epicanthic folds. The cat-like cry is the most prominent clinical characteristic in newborn children and is usually considered as diagnostic for the CDC syndrome. Using a strategy of 'phenotype dissection', the critical region for cat-like cry was mapped to the chromosomal segment 5p15.3-5p15.2 in previous reports. In this study, the distal breakpoints of two interstitial deletions in two clinical distinctive CDC patients are analysed, one with and one without the cat-like cry. Using PCR, the critical region for the cat-like cry is mapped to a short 640 kbp region on chromosome 5p. Genome analysis of this critical region reveals a gene-rich sequence containing five known genes, five putative genes and three spliced EST sequences, altogether 71 predicted exons. Three genes, FLJ25076, a homolog to a ubiquitin-conjugating enzyme UBC-E2, FLJ20303, a nucleolar protein NOP2, which may play a role in the regulation of the cell cycle and MGC5309, a protein with similarity to Nut2, a Drosophila transcriptional coactivator, have been characterized and expression profiles determined by quantitative PCR. These results suggest that one candidate gene, FLJ25076, encodes a ubiquitin-conjugated enzyme E2 type, which is locally expressed in thoracic and scalp tissues. The other two genes are expressed uniformly in all tissues tested, which suggest that they are housekeeping genes.
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PMID:Determination of the 'critical region' for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR. 1565 23

ARIP4 [AR (androgen receptor)-interacting protein 4] is a member of the SNF2-like family of proteins. Its sequence similarity to known proteins is restricted to the centrally located SNF2 ATPase domain. ARIP4 is an active ATPase, and dsDNA (double-stranded DNA) and ssDNA (single-stranded DNA) enhance its catalytic activity. We show in the present study that ARIP4 interacts with AR and binds to DNA and mononucleosomes. The N-terminal region of ARIP4 mediates interaction with AR. Kinetic parameters of the ARIP4 ATPase are similar to those of BRG-1 and SNF2h, two members of the SNF2-like protein family, but the specific activity of ARIP4 protein purified to >90% homogeneity is approximately ten times lower, being 120 molecules of ATP hydrolysed by an ARIP4 molecule per min in contrast with approx. 1000 ATP molecules hydrolysed per min by ATP-dependent chromatin remodellers. Unlike other members of the SNF2 family, ARIP4 does not appear to form large protein complexes in vivo or remodel mononucleosomes in vitro. ARIP4 is covalently modified by sumoylation, and mutation of six potential SUMO (small ubiquitin-related modifier) attachment sites abolished the ability of ARIP4 to bind DNA, hydrolyse ATP and activate AR function. We conclude that, similar to its closest homologues in the SNF2-like protein family, ATRX (alpha-thalassemia, mental retardation, X-linked) and Rad54, ARIP4 does not seem to be a classical chromatin remodelling protein.
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PMID:Biochemical characterization of androgen receptor-interacting protein 4. 1621 58

Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. We mapped the disease-associated locus to chromosome 15q14-21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1(-/-) mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.
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PMID:Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). 1631 97

The devastating nature and lack of effective treatments associated with neurodegenerative diseases have stimulated a world-wide search for the elucidation of their molecular basis to which mouse models have made a major contribution. In combination with transgenic and knockout technologies, large-scale mouse mutagenesis is a powerful approach for the identification of new genes and associated signalling pathways controlling neuronal cell death and survival. Here we review the characterization of the robotic mouse, a novel model of autosomal dominant cerebellar ataxia isolated from an ENU-mutagenesis programme, which develops adult-onset region-specific Purkinje cell loss and cataracts, and displays defects in early T-cell maturation and general growth retardation. The mutated protein, Af4, is a member of the AF4/LAF4/FMR2 (ALF) family of putative transcription factors previously implicated in childhood leukaemia and FRAXE mental retardation. The mutation, which lies in a highly conserved region among the ALF family members, significantly reduces the binding affinity of Af4 to the E3 ubiquitin-ligase Siah-1a, isolated with Siah-2 as interacting proteins in the brain. This leads to a markedly slower turnover of mutant Af4 by the ubiquitin-proteasome pathway and consequently to its abnormal accumulation in the robotic mouse. Importantly, the conservation of the Siah-binding domain of Af4 in all other family members reveals that Siah-mediated proteasomal degradation is a common regulatory mechanism that controls the levels, and thereby the function, of the ALF family. The robotic mouse represents a unique model in which to study the newly revealed role of Af4 in the maintenance of vital functions of Purkinje cells in the cerebellum and further the understanding of its implication in lymphopoeisis.
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PMID:The robotic mouse: unravelling the function of AF4 in the cerebellum. 1632 81

We report a mutation of UBE2A/HR6A, which encodes a ubiquitin-conjugating enzyme (E2), a member of the ubiquitin proteasome pathway, as the cause of a novel X-linked mental retardation (XLMR) syndrome that affects three males in a two-generation family. A single-nucleotide substitution, c.382C-->T in UBE2A, led to a premature UAG stop codon (Q128X). As a consequence, the predicted polypeptide lacks the 25 C-terminal amino acid residues. The importance of this terminal sequence for UBE2 function is inferred by its conservation in vertebrates and in Drosophila. UBE2A mutations do not appear to significantly contribute to XLMR, since no UBE2A mutations were identified in 15 families with nonsyndromic and 4 families with syndromic idiopathic XLMR previously mapped to intervals encompassing this gene. This is the first description of a mutation in a ubiquitin-conjugating enzyme gene as the cause of a human disease.
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PMID:UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a novel X-linked mental retardation syndrome. 1690 93

We report the case of a 54-year-old woman with mental retardation who developed frontotemporal dementia and amyotrophic lateral sclerosis (ALS) in the presenium. She presented with dementia at age 48, and motor neuron signs developed at age 53. She had no family history of dementia or ALS. Postmortem examination disclosed histopathological features of ALS, including pyramidal tract degeneration, mild loss of motor neurons, and many Bunina bodies immunoreactive for cystatin C, but not ubiquitin-positive inclusions. Unusual features of this case included severe neuronal loss in the substantia nigra and medial globus pallidus. The subthalamic nucleus, limbic system, and cerebral cortex were well preserved. In addition, neurofibrillary tangles (NFTs) were found in the frontal, temporal, insular, and cingulate cortices, nucleus basalis of Meynert, and locus coeruleus, and to a lesser degree, in the dentate nucleus, cerebellum, hippocampus, and amygdala. No ballooned neurons, tufted astrocytes, or astrocytic plaques were found. Tau immunostaining demonstrated many pretangles rather than NFTs and glial lesions resembling astrocytic plaques in the frontal and temporal cortices. This glial tau pathology predominantly developed in the middle to deep layers in the primary motor cortex, and was frequently associated with the walls of blood vessels. NFTs were immunolabeled with 3-repeat and 4-repeat specific antibodies against tau, respectively. Although the pathophysiological relationship between tau pathology and the selective involvement of motor neurons, substantia nigra, and globus pallidus was unclear, we considered that it might be more than coincidental.
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PMID:Amyotrophic lateral sclerosis with dementia: an autopsy case showing many Bunina bodies, tau-positive neuronal and astrocytic plaque-like pathologies, and pallido-nigral degeneration. 1702 51


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