PubMed Health⌕ Search

Biomedical subjects

R Matalon

Publications and source records attributed to R Matalon.

At least 55 records · Page 3Linked to original sources
PubMed1996

Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease.

Canavan disease is inherited as an autosomal recessive trait that is caused by the deficiency of aspartoacylase (ASPA). The majority of patients with Canavan disease are from an Ashkenazi Jewish background. Mutations in ASPA that lead to loss of enzymatic activity have been identified, and E285A and Y231X are the two predominant mutations that account for 97% of the mutant chromosomes in Ashkenazi Jewish patients. The current study was aimed at finding the molecular basis of Canavan disease in 25 independent patients of non-Jewish background. Eight novel and three previously characterized mutations accounted for 80% (40/50) of mutant chromosomes. The A305E missense mutation accounted for 48% (24/50) of mutant chromosomes in patients of western European descent, while the two predominant Jewish mutations each accounted for a single mutant chromosome. The eight novel mutations identified included 1- and 4-bp deletions (32 deltaT and 876 deltaAGAA, respectively) and I16T, G27R, D114E, G123E, C152Y, and R168C missense mutations. The homozygous 32 deltaT deletion was identified in the only known patient of African-American origin with Canavan disease. The heterozygosity for 876 deltaAGAA mutation was identified in three independent patients from England. Six single-base changes leading to missense mutations were identified in patients from Turkey (D114E, R168C), The Netherlands (I16T), Germany (G27R), Ireland (C152Y), and Canada (G123E). A PCR-based protocol is described that was used to introduce mutations in wild-type cDNA. In vitro expression of mutant cDNA clones demonstrated that all of these mutations led to a deficiency of ASPA and should therefore result in Canavan disease.

Amidohydrolases↗
PubMed1995

Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency.

GTP cyclohydrolase I is the first and rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin in mammals. Previously, we reported three species of human GTP cyclohydrolase I cDNA in a human liver cDNA library (Togari, A., Ichinose, H., Matsumoto, S., Fujita, K., and Nagatsu, T. (1992) Biochem. Biophys. Res. Commun. 187, 359-365). Furthermore, very recently, we found that the GTP cyclohydrolase I gene is causative for hereditary progressive dystonia with marked diurnal fluctuation, also known as DOPA-responsive dystonia (Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., and Nagatsu, T. (1994) Nature Genetics 8, 236-242). To clarify the mechanisms that regulate transcription of the GTP cyclohydrolase I gene and to generate multiple species of mRNA, we isolated genomic DNA clones for the human and mouse GTP cyclohydrolase I genes. Structural analysis of the isolated clones revealed that the GTP cyclohydrolase I gene is encoded by a single copy gene and is composed of six exons spanning approximately 30 kilobases. We sequenced all exon/intron boundaries of the human and mouse genes. Structural analysis also demonstrated that the heterogeneity of GTP cyclohydrolase I mRNA is caused by an alternative usage of the splicing acceptor site at the sixth exon. The transcription start site of the mouse GTP cyclohydrolase I gene and the 5'-flanking sequences of the mouse and human genes were determined. We performed regional mapping of the mouse gene by fluorescence in situ hybridization, and the mouse GTP cyclohydrolase I gene was assigned to region C2-3 of mouse chromosome 14. We identified missense mutations in patients with GTP cyclohydrolase I deficiency and expressed mutated enzymes in Escherichia coli to confirm alterations in the enzyme activity.

Amino Acid Sequence↗
PubMed1995

Canavan disease: from spongy degeneration to molecular analysis.

Establishing the basic defect in Canavan disease has led to reliable biochemical methods for the diagnosis of this disease. The isolation of the gene and identification of mutations causing Canavan disease have led to the possibility of using DNA methods for the diagnosis of Canavan disease and for carrier detection. A surprising finding is the high carrier frequency of this gene defect among Ashkenazi Jewish people. Analysis for two mutations leads to the identification of 97% of Jewish patients with Canavan disease, and screening of Ashkenazi Jews is possible. N-Acetylaspartic acid has been considered to be an inert compound. The pathophysiology of Canavan disease links lack of NAA hydrolysis to a severe, debilitating white matter disease. Currently, NAA is being studied in many other brain disorders, such as Alzheimer disease, Huntington disease, and stroke. However, the only disease with a specific defect in the metabolism of NAA is Canavan disease. An animal model for Canavan disease is needed to study some of the questions regarding the role of NAA in brain tissue, and for the study of therapeutic modalities, including gene therapy.

Age of Onset↗
PubMed1995

Overexpression of arylsulfatase A gene in fibroblasts from metachromatic leukodystrophy patients does not induce a new phenotype.

We tested the influence of overexpression of arylsulfatase A (ASA) on the activity of other sulfatases in fibroblasts from patients with metachromatic leukodystrophy (MLD). We demonstrated that the overexpression of ASA reduces the activity of various sulfatases by a small amount but does not induce an accumulation of glycosaminoglycan. Our results indicate that influence of ASA overexpression on other sulfatases is different from that of N-acetyl-galactosamine-4-sulfatase overexpression reported by Anson et al. We conclude that gene therapy for MLD based on the transfer of a normal ASA gene to mutant cells will be feasible because the overexpression of ASA peptides in cells does not lead to profound deficiency of other sulfatases or result in a new phenotype.

Cells, Cultured↗
PubMed1994

Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.

Canavan disease, or spongy degeneration of the brain, is a severe leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Recently, a missense mutation was identified in human ASPA coding sequence from patients with Canavan disease. The human ASPA gene has been cloned and found to span 29 kb of the genome. Human aspartoacylase is coded by six exons intervened by five introns. The exons vary from 94 (exon III) to 514 (exon VI) bases. The exon/intron splice junction sites follow the gt/ag consensus sequence rule. Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines localized ASPA to human chromosome 17. The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization. The bovine aspa gene has also been cloned, and its exon/intron organization is identical to that of the human gene. The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical. Human ASPA coding sequences cross-hybridize with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey. The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution. It should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan disease and to study the regulation of ASPA.

Amidohydrolases↗
PubMed1994

Lipoprotein glomerulopathy: first report in a Chinese male.

Only seven patients with lipoprotein glomerulopathy have been reported, all in Japanese subjects. We describe the first Chinese patient with lipoprotein glomerulopathy, a 28-year-old man followed for 8 years. As in all patients described thus far, our patient has hyperlipoproteinemia phenotypically similar to the familial type III hyperlipoproteinemia, a high serum level of apolipoprotein E (apo E) (but with the heterozygous E 2/3 isoform instead of the E 2/2 isoform), and the absence of the typical clinical features associated with type III hyperlipoproteinemia. The common clinical presentation is the nephrotic syndrome. The characteristic pathologic features are concentrically layered vacuolated lipid "thrombi" in distended glomerular capillary lumens that contain beta/pre-beta lipoprotein. Immunofluorescence studies demonstrate lipoprotein "thrombi" staining for apo E and apo B, but not apo A-I, apo A-II, or apo J. Immunoglobulins, complement, and fibrin are absent or present in trace amounts. The long-term follow-up demonstrates progressive deterioration of renal function despite lipolytic therapy. The apparent predilection of lipoprotein glomerulopathy in Orientals, particularly Japanese subjects, is poorly understood, but appears to be related to genetic factors. The cause of the hyperlipoproteinemia and lipoprotein "thrombi" containing apo E and apo B is unknown, but is possibly related to defective receptor-binding mechanisms.

Adult↗
PubMed1994

The international collaborative study of maternal phenylketonuria: status report 1994.

Neonatal screening for phenylketonuria (PKU) has created a problem as females with PKU are reaching child-bearing age. Surveys have revealed that maternal phenylalanine blood concentrations greater than 1200 mumol/l are associated with fetal microcephaly, congenital heart defects and intrauterine growth retardation. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk of producing these fetal abnormalities. To examine this problem, the international maternal PKU collaborative study was developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings have indicated that phenylalanine restriction should begin before conception for females with PKU planning a pregnancy. Dietary control should maintain maternal blood phenylalanine levels between 120 and 360 mumol/l and should provide adequate energy, protein, vitamin and mineral intake. Pregnant hyperphenylalaninemic females who achieved metabolic control after conception or by the 10th week of pregnancy had a better offspring outcome than anticipated. The results of 402 pregnancies are reviewed.

Adult↗
PubMed1994

Canavan disease: mutations among Jewish and non-Jewish patients.

Canavan disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyzed for mutations in the ASPA gene. Three point mutations--693C-->A, 854A-->C, and 914C-->A--were identified in the coding sequence. The 693C-->A and 914C-->A base changes, resulting in nonsense tyr231-->ter and missense ala305-->glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies. The 854A-->C transversion converted glu to ala in codon 285. The glu285-->ala mutant ASPA has 2.5% of the activity expressed by the wild-type enzyme. A fourth mutation, 433 --2(A-->G) transition, was identified at the splice-acceptor site in intron 2. The splice-site mutation would lead to skipping of exon 3, accompanied by a frameshift, and thus would produce aberrant ASPA. Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The glu285-->ala mutation was predominant (82.9%) in this population, followed by the tyr231-->ter (14.8%) and 433 --2(A-->G) (1.1%) mutations. The three mutations account for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin. The ala305-->glu mutation was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes. Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan disease would suggest a founding-father effect in propagation of these mutant chromosomes.

Amidohydrolases↗
PubMed1993

The North American Collaborative Study of Maternal Phenylketonuria. Status report 1993.

Neonatal screening for phenylketonuria (PKU) has created an unexpected problem as females with PKU are reaching childbearing age. Surveys have revealed that maternal phenylalanine blood concentrations above 1200 mumol/L are associated with microcephaly, mental retardation, congenital heart defects, and intrauterine growth retardation among their offspring. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk for producing these fetal abnormalities. To examine this problem, the North American Maternal PKU Collaborative Study has been developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings indicate that phenylalanine restriction should begin before conception for females with PKU planning a pregnancy. Dietary control should maintain maternal blood phenylalanine levels between 120 and 360 mumol/L and should provide adequate energy, protein, vitamin, and mineral intake. Pregnant hyperphenylalaninemic females who achieved metabolic control after conception or by the 10th week of pregnancy had a better offspring outcome than anticipated.

Adolescent↗
PubMed1993

Canavan disease: biochemical and molecular studies.

Deficiency of the enzyme aspartoacylase and the accumulation of N-acetylaspartic acid lead to a severe leukodystrophy and spongy degeneration of the brain, Canavan disease (McKusick 271900). Since our discovery in 1988 of the defect in Canavan disease, 144 patients with Canavan disease have been diagnosed in our laboratory. Most of these children are of Ashkenazi Jewish extraction. The level of enzyme activity can be used for carrier testing. Prenatal diagnosis has been difficult using the enzyme assay owing to the low activity of aspartoacylase in cultured chorionic villus samples or amniocytes. The determination of N-acetylaspartic acid in the amniotic fluid is another parameter for diagnosis; however, the levels may not always be elevated. Bovine and human aspartoacylase have been purified in our laboratory. Bovine and human cDNA and genomic clones have been isolated and six exons have been localized. This information is being used for the study of Canavan disease at the molecular level.

Amidohydrolases↗
PubMed1993

Prospective management of a child with neonatal citrullinemia.

A patient with neonatal citrullinemia caused by severe deficiency of argininosuccinate synthetase was treated prospectively according to the currently accepted protocol. We gradually reduced the doses and then discontinued treatment with sodium benzoate and phenylacetate; blood glutamine levels were maintained in the normal range, but ammonia was mildly elevated. Growth and development progressed normally through 31 months of age. Some patients with citrullinemia can be successfully managed without daily sodium benzoate and phenylacetate therapy.

Amino Acid Metabolism, Inborn Errors↗