Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible relationship between the metachromatic leukodystrophies and neuropsychiatric disorders is reviewed. Four kinds of evidence are considered: psychiatric symptoms as preemergent markers of the neurodegenerative process; increased behavioral problems in leukodystrophy families; screening for low enzyme levels among psychiatric populations; and studies in model systems. Whereas the basic postulate of an increased risk for psychiatric problems among individuals with lower levels of the enzymes deficient in the leukodystrophies remains attractive, there is no strong evidence in its support. Low enzyme levels can be found in psychiatric populations, but they may not be any more frequent than in the general population.
Mol Chem Neuropathol
PMID:The relationship of the metachromatic leukodystrophies to neuropsychiatric disorders. 198 80

N-acetyl-L-aspartate (NAA) is an important osmolyte in the vertebrate brain and eye, and its cyclical metabolism is accomplished in two separate compartments. In the brain, NAA is synthesized primarily in neurons, and after its regulated release, NAA is hydrolyzed by aspartoacylase, which is present in a glial-associated compartment. However, the precise nature of this hydrolytic compartment has remained obscure. It has been proposed that one role of aspartoacylase in the central nervous system (CNS) is as part of a molecular water pump (MWP) that uses the NAA intercompartmental cycle to remove nerve cell metabolic water against a water gradient and that oligodendrocytes comprise the second compartment in this metabolic sequence. The absence of aspartoacylase activity in Canavan disease (CD), a rare early onset genetic spongiform leukodystrophy, is associated with CNS edema, intramyelinic swelling and a progressive loss of oligdendrocytes. In order to evaluate the MWP hypothesis and its possible relationship to the etiology of CD further, both oligodendrocytes and astrocytes obtained from neonatal rat brain were grown in culture and tested for the presence of aspartoacylase activity. The results of this study show for the first time that aspartoacylase activity is expressed only in oligodendrocytes. The meaning of this observation in understanding the function of the NAA metabolic cycle is discussed.
J Mol Neurosci
PMID:Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes. 1069 Dec 91

The hereditary leukodystrophies represent a group of neurological disorders, in which complete or partial dysmyelination occurs in either the central nervous system (CNS) and/or the peripheral nervous system. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, and the phenotype is similar to that of chronic progressive multiple sclerosis. We report clinical, neuroradiological and neuropathological data from the originally reported ADLD family. Furthermore, we have localized the gene that causes ADLD to a 4 cM region on chromosome 5q31. Linkage analysis of this family yielded a LOD score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. Genetic localization will lead to cloning and characterization of the ADLD gene and may yield new insights into myelin biology and demyelinating diseases.
Hum Mol Genet 2000 Mar 22
PMID:Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31. 1074 86

Canavan disease (CD) is a globally distributed early-onset leukodystrophy. It is genetic in nature, and results from an autosomally inherited recessive trait that is characterized by loss of the axon's myelin sheath while leaving the axons intact, and spongiform degeneration especially in white matter. There is also a buildup of N-acetyl-L-aspartate (NAA) in brain, as well as NAA acidemia and NAA aciduria. The cause of the altered NAA metabolism has been traced to several mutations in the gene for the production of aspartoacylase, located on chromosome 17, which is the primary enzyme involved in the catabolic metabolism of NAA. In this review, an attempt is made to correlate the change in NAA metabolism that results from the genetic defects in CD with the processes involved in the development of the CD syndrome. In addition, present efforts to counter the results of the genetic defects in this disease are also considered.
J Mol Neurosci 2000 Oct
PMID:Canavan's spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease. 1122 Jul 86

Sphingolipid activator proteins (saposins A, B, C and D) are small homologous glycoproteins derived from a common precursor protein (prosaposin) encoded by a single gene. They are required for in vivo degradation of sphingolipids with short carbohydrate chains. Six cysteines and one glycosylation site are strictly conserved in all four saposins. Total deficiency of all saposins and specific deficiency of saposin B or C are known among human patients. A mouse model of total saposin deficiency closely mimics the human disease. However, no specific saposin A or D deficiency is known. We introduced an amino acid substitution (C106F) into the saposin A domain by the Cre/loxP system which eliminated one of the three conserved disulfide bonds. Saposin A(-/-) mice developed slowly progressive hind leg paralysis with clinical onset at approximately 2.5 months and survival up to 5 months. Tremors and shaking, prominent in other myelin mutants, were not obvious until the terminal stage. Pathology and analytical biochemistry were qualitatively identical to, but generally much milder than, that seen in the typical infantile globoid cell leukodystrophy (GLD) in man (Krabbe disease) and in several other mammalian species, due to genetic deficiency of lysosomal galactosylceramidase (GALC) (EC 3.2.1.46). Thus, saposin A is indispensable for in vivo degradation of galactosylceramide by GALC. It should now be recognized that, in addition to GALC deficiency, genetic saposin A deficiency could also cause chronic GLD. Genetic saposin A deficiency might be anticipated among human patients with undiagnosed late-onset chronic leukodystrophy without GALC deficiency.
Hum Mol Genet 2001 May 15
PMID:A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse. 1137 12

Globoid cell leukodystrophy (Krabbe disease) is a severe leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene leading to extremely low (less than 5% of normal activity) GALC activity. Human patients include primarily severely affected infants as well as patients with a later onset of symptoms. The infants usually die before 2 years of age, but it is difficult to predict the clinical course in older patients. In addition to these patients, additional individuals identified in this laboratory have 10--20% of normal GALC activity measured in accessible tissues. These individuals have a wide range of clinical presentations involving neurological degeneration. On molecular analysis of the GALC gene they all have three or more mutations considered to be normal polymorphisms resulting in amino acid changes in the two copies of the GALC gene. In order to investigate the role these amino acid changes may play on clinical, biochemical, and pathological findings, a new transgenic mouse was generated by homologous recombination. After preliminary studies determined what effect each amino acid change had on mouse GALC activity in transient transfection experiments, mice containing a cysteine residue at codon 168 instead of histidine (H168C) were produced. These mice developed symptoms, but they were delayed by 10--15 days from the well-characterized twitcher (twi) mouse. They accumulated psychosine slightly slower than twi mice, showed pathological changes less severe than twi mice in the central and peripheral nervous systems, and live about 15 days longer than twi mice. They have large litters and will play a role in therapy trials using new procedures currently under development.
Mol Genet Metab 2001 Jul
PMID:Generation of a mouse with low galactocerebrosidase activity by gene targeting: a new model of globoid cell leukodystrophy (Krabbe disease). 1146 Nov 88

The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant adeno-associated virus (AAV) vectors.
Curr Opin Mol Ther 1999 Aug
PMID:Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease. 1171 64

Autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare childhood-onset spongiform leukodystrophy with macrocephaly and slowly progressive deterioration of motor functions. Mutations in KIAA0027/MLC1 have recently been found associated with MLC, and a high degree of allelic heterogeneity has been observed. In addition, initial reports suggested that a rare variant in exon 11 (L309M) is involved in the etiology of schizophrenia, but recent studies have brought forward compelling arguments that genetic variants of MLC1 are not associated with schizophrenia. Using DHPLC-analysis, reproduction of previous findings on L309M revealed homoduplex resolution patterns among individuals, who had been described to be heterozygous for the variant, which was further confirmed by sequencing the respective PCR products. Cumulative effects of high GC content, secondary folding structures due to incomplete intronic tandem-repeats, and a complicated insertion polymorphism at the 3-end of exon 11 may be the cause of preferential amplification of specific alleles of exon 11. Consistent amplification was obtained only when we employed exonic primers directly adjacent to the L309M variant. For mutational screening, we propose a two-step test: (1) testing for the 33 bp insertion polymorphism of exon 11, and (2) amplification of the exon using different primer sets depending on the presence or absence of the insertion.
Mol Cell Probes 2002 Oct
PMID:Reduced amplification efficiency of KIAA0027/MLC1 alleles: implications for the molecular diagnosis of megalencephalic leukoencephalopathy with subcortical cysts. 1247 42

Canavan disease (CD) is an autosomal recessive leukodystrophy caused by deficiency of aspartoacylase (ASPA). Deficiency of ASPA leads to elevation of N-acetyl-L-aspartic acid (NAA) in the brain and urine. To explore the feasibility of gene transfer to replace ASPA in CD, we generated a knockout mouse and constructed an AAV vector that encodes human ASPA cDNA (hASPA) followed by green fluorescent protein (GFP) after an intraribosomal entry site. We injected CD mice with rAAV-hASPA-GFP in the striatum and thalamus or injected rAAV-GFP identically into control animals. Three to five months after the injection, we determined the presence of ASPA in the CD mouse brain by ASPA activity assay, GFP expression, and Western blot analysis. While rAAV-GFP-injected animals displayed undetectable levels of ASPA, all detection methods revealed significant ASPA levels in rAAV-hASPA-GFP-injected CD mice. We evaluated the functional effects of rAAV-hASPA-GFP-mediated ASPA expression by standard histological methods, magnetic resonance spectroscopy (MRS) for in vivo NAA levels, and magnetic resonance imaging of CD mice. rAAV-hASPA-injected animals displayed a remarkable lack of spongiform degeneration in the thalamus. However, pathology in sites unrelated to the injected areas showed no improvement in histopathology. The improvement in thalamic neuropathology was also detectable via in vivo MRI. MRS revealed that in vivo NAA levels were also reduced. These data indicate that rAAV-mediated ASPA delivery may be an interesting avenue for the treatment of CD.
Mol Ther 2003 May
PMID:Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease. 1271

Deficiencies in the activity of cytochrome c oxidase (COX) are an important cause of autosomal recessive respiratory chain disorders. Patients with isolated COX deficiency are clinically and genetically heterogeneous, and mutations in several different assembly factors have been found to cause specific clinical phenotypes. Two of the most common clinical presentations, Leigh Syndrome and hypertrophic cardiomyopathy, have so far only been associated with mutations in SURF1 or SCO2 and COX15, respectively. Here we show that expression of COX10 from a retroviral vector complements the COX deficiency in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy. A partial rescue was also obtained following microcell-mediated transfer of mouse chromosomes into patient fibroblasts. COX10 functions in the first step of the mitochondrial heme A biosynthetic pathway, catalyzing the conversion of protoheme (heme B) to heme O via the farnesylation of a vinyl group at position C2. Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme. Mutation analysis of COX10 identified four different missense alleles, predicting amino acid substitutions at evolutionarily conserved residues. A topological model places these residues in regions of the protein shown to have important catalytic functions by mutation analysis of a prokaryotic ortholog. Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy. This study shows that mutations in this gene can cause nearly the full range of clinical phenotypes associated with early onset isolated COX deficiency.
Hum Mol Genet 2003 Oct 15
PMID:Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. 1292 84


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