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

We have examined the molecular basis of three cases of severe mental retardation with autistic features in one family. A point mutation in a purine nucleotide biosynthetic enzyme, adenylosuccinate lyase (ASL), segregates with the disorder. The affected children are homozygous for the point mutation while the parents and all four unaffected children are heterozygous. The point mutation is absent in control subjects. The point mutation results in a Ser413Pro substitution which leads to structural instability of the recombinant mutant enzyme, and this instability lowers ASL levels in lymphocytes. These observations suggest that the instability of ASL underlies the severe developmental disorder in the affected children, and that mutations in the ASL gene may result in other cases of mental retardation and autistic features.
 ...
PMID:A mutation in adenylosuccinate lyase associated with mental retardation and autistic features. 130 1

Adenylosuccinate adenosine 5'-monophosphate lyase (EC 4.3.2.2; ASL) catalyzes two distinct reactions in adenosine 5'-monophosphate (AMP) biosynthesis. A S413P mutation in ASL segregates with mental retardation in an affected family (Stone, R. L., Aimi, J., Barshop, B. A., Jaeken, J., Van den Berghe, G., Zalkin, H., and Dixon, J. E. (1992) Nature Genet. 1, 59-63). ASL and S413P ASL have been expressed, purified, and kinetically characterized. Lowering the Escherichia coli growth temperature to 25 degrees C and the concentration of inducer, isopropyl-1-thio-beta,D-galactopyranoside, to 40 microM was necessary for synthesis of soluble, tetrameric enzymes. The recombinant enzymes were purified to homogeneity using anion exchange chromatography followed by chromatography on Blue 2A Sepharose. At pH 7.0 and 25 degrees C, the kcat for cleavage of 5-amino-4-imidazole-N-succinocarboxamide ribotide (SAI-CAR) by ASL was 90 s-1 with a Km of 2.35 microM. The kcat for adenylosuccinate (SAMP) cleavage was 97 s-1 with a Km of 1.79 microM. The catalytic mechanism involved one general base catalyst (pK alpha = 6.4) and one general acid catalyst (pK alpha = 7.5). ASL follows an ordered uni-bi reaction mechanism with fumarate released first. 5-Amino-4-imidazolecarboxamide ribotide (AICAR) and AMP were competitive with SAICAR and SAMP (Ki[AICAR] = 11.3 microM; Ki[AMP] = 9.2 microM), whereas fumarate inhibited noncompetitively (Kii = 2.3 mM, Kis = 2.8 mM). The competitive inhibition by AICAR and AMP suggests a single active site that binds both SAICAR and SAMP. The kinetic constants at pH 7.0, 25 degrees C and the kcat/Km versus pH profiles for ASL and S413P ASL were very similar. These results are consistent with S413P being a structural rather than a catalytic defect.
 ...
PMID:Expression, purification, and kinetic characterization of recombinant human adenylosuccinate lyase. 836 12

A modelling approach is used to analyse diseases associated with purine metabolism in man. The specific focus is on deficiencies in two enzymes, hypoxanthine:guanine phosphoribosyltransferase and adenylosuccinate lyase. These deficiencies can lead to a number of symptoms, including neurological dysfunctions and mental retardation. Although the biochemical mechanisms of dysfunctions associated with adenylosuccinate lyase deficiency are not completely understood, there is at least general agreement in the literature about possible causes. Simulations with our model confirm that accumulation of the two substrates of the enzyme can lead to significant biochemical imbalance. In hypoxanthine:guanine phosphoribosyltransferase deficiency the biochemical mechanisms associated with neurological dysfunctions are less clear. Model analyses support some old hypotheses but also suggest new indicators for possible causes of neurological dysfunctions associated with this deficiency. Hypoxanthine:guanine phosphoribosyltransferase deficiency is known to cause hyperuricaemia and gout. We compare the relative importance of this deficiency with other known causes of gout in humans. The analysis suggests that defects in the excretion of uric acid are more consequential than defects in uric acid synthesis such as hypoxanthine:guanine phosphoribosyltransferase deficiency.
 ...
PMID:Analysis of abnormalities in purine metabolism leading to gout and to neurological dysfunctions in man. 944 73

Adenylosuccinate lyase catalyzes two separate reactions in the de novo purine biosynthetic pathway. Through its dual action in this pathway, adenylosuccinate lyase plays an integral part in cellular replication and metabolism. Mutations in the human enzyme can result in severe neurological disorders, including mental retardation with autistic features. The crystal structure of adenylosuccinate lyase from the hyperthermophilic archaebacterium Pyrobaculum aerophilum has been determined to 2.1 A resolution. Although both the fold of the monomer and the architecture of the tetrameric assembly are similar to adenylosuccinate lyase from the thermophilic eubacterium Thermotoga maritima, the archaebacterial lyase contains unique features. Surprisingly, the structure of adenylosuccinate lyase from P. aerophilum reveals that this intracellular protein contains three disulfide bonds that contribute significantly to its stability against thermal and chemical denaturation. The observation of multiple disulfide bonds in the recombinant form of the enzyme suggests the need for further investigations into whether the intracellular environment of P. aerophilum, and possibly other hyperthermophiles, may be compatible with protein disulfide bond formation. In addition, the protein is shorter in P. aerophilum than it is in other organisms. This abbreviation results from an internal excision of a cluster of helices that may be involved in protein-protein interactions in other organisms and may relate to the observed clinical effects of human mutations in that region.
 ...
PMID:The crystal structure of adenylosuccinate lyase from Pyrobaculum aerophilum reveals an intracellular protein with three disulfide bonds. 1092 19

We report on the striking variable expression of adenylosuccinate lyase (ADSL) deficiency in three patients belonging to a family which originates from Portugal. ADSL deficiency is a rare autosomal recessive disorder of the de novo purine synthesis which results in accumulation of succinylpurines in body fluids. As a result, patients may have variable combinations of psychomotor retardation and/or regression, seizures, autistic features and cerebellar vermis hypoplasia. However, intrafamilial variable expression of the phenotype has not been documented to date in this disease and is not commonly observed in metabolic disorders. Here, while the proband had marked psychomotor regression and progressive cerebellar vermis atrophy, the other two affected patients presented mainly autistic features. Mutation analysis of the ADSL gene revealed the presence of a homozygous R426H mutation in this family. Finally, although ADSL deficiency is a rare disorder, this diagnosis should be considered and assessed using a simple urinary screening method for the presence of succinylpurines in any patient with mental retardation of unexplained origin.
 ...
PMID:Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients. 1283 98

The genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), located on the X chromosome, causes a severe neurological disorder in man, known as Lesch-Nyhan disease (LND). The enzyme HPRT is part of the savage pathway of purine biosynthesis and catalyzes the conversion of hypoxanthine and guanine to their respective nucleotides, IMP and GMP. HPRT deficiency is associated with a relatively selective dysfunction of brain dopamine systems. Several metabolites that accumulate in the patients (phosphoribosylpyrophosphate (PRPP), hypoxanthine, guanine, xanthine, and Z-nucleotides) have been proposed as toxic agents in LND. Some authors have pointed that Z-riboside, derived from the accumulation of ZMP, could be the toxic metabolite in LND. However, the available experimental data support a better hypothesis. I suggest that ZMP (and not Z-riboside) is the key toxic metabolite in LND. ZMP is an inhibitor of the bifunctional enzyme adenylosuccinate lyase, and a deficiency of this enzyme causes psychomotor and mental retardation in humans. Moreover, it has been reported that ZMP inhibits mitochondrial oxidative phosphorylation and induces apoptosis in certain cell types. ZMP is also an activator of the AMP-activated protein kinase (AMPK), a homeostatic regulator of energy levels in the cell. The AMPK has been implicated in the regulation of cell viability, catecholamine biosynthesis and cell structure. I propose that accumulation of ZMP will induce a pleiotropic effect in the brain by (1) a direct inhibition of mitochondrial respiration and the bifunctional enzyme adenylosuccinate lyase, and (2) a sustained activation of the AMPK which in turns would reduce cell viability, decrease dopamine synthesis, and alters cell morphology. In addition, a mechanism to explain the accumulation of ZMP in LND is presented. The knowledge of the toxic metabolite, and the way it acts, would help to design a better therapy.
 ...
PMID:Is ZMP the toxic metabolite in Lesch-Nyhan disease? 1871 Jul 92

Adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features and are usually discovered during screens for unexplained encephalopathy using the Bratton-Marshall assay that reveals the excretion of the succinylaminoimidazolecarboxamide riboside (SAICAr). Here, we report on two sisters aged 11 and 12 years presented with global developmental delay, motor apraxia, severe speech deficits, seizures and behavioural features, which combined excessive laughter, a very happy disposition, hyperactivity, a short attention span, the mouthing of objects, tantrums and stereotyped movements that gave a behavioural profile mimicking Angelman syndrome. Both patients had an increased succinyladenosine/SAICAr ratio of 1.6, and exhibited a novel homozygous missense mutation (c.674T>C; p.Met225Thr) in the exon 6 of the ADSL gene. We suggest that these clinical features might be a new presentation of adenylosuccinate lyase deficiency. On the basis of this observation, although adenylosuccinate lyase deficiency is a rare disorder, this diagnosis should be considered in patients with mental retardation and a behavioural profile suggestive of Angelman syndrome.
 ...
PMID:Misleading behavioural phenotype with adenylosuccinate lyase deficiency. 1883 Feb 28

Mental retardation (MR) is a common disorder frequently of unknown origin. Because there are few studies regarding MR and inborn errors of metabolism (IEM), we aimed to identify patients with IEM from a cohort of 944 patients with unexplained MR. Biochemical examinations such as determination of creatine (Cr) metabolites, acylcarnitines, purine, and pyrimidines in urine were applied. We found seven patients with IEM [three with cerebral Cr deficiency syndromes (CCDS)], one with adenylosuccinate lyase (ADSL) deficiency, and three, born before the neonatal metabolic screening program in Catalonia, with phenylketonuria (PKU). All told, they represent 0.8% of the whole cohort. All of them had additional symptoms such as epilepsy, movement disorders, autism, and other psychiatric disturbances. In conclusion, in patients with MR, it is essential to perform a thorough appraisal of the associated signs and symptoms, and in most disorders, it is necessary to apply specific analyses. In some cases, it is important to achieve an early diagnosis and therapy, which may reduce the morbimortality, and to offer genetic counselling.
 ...
PMID:Study of inborn errors of metabolism in urine from patients with unexplained mental retardation. 2004 33