A5089467508- Porphyrin Metabolism and Disorders
- Folate and B Vitamins Research
- Neonatal Health and Biochemistry
- Heme Oxygenase-1 and Carbon Monoxide
- Lysosomal Storage Disorders Research
- Carbohydrate Chemistry and Synthesis
- Cellular transport and secretion
- Trypanosoma species research and implications
- Metabolism and Genetic Disorders
- Glycosylation and Glycoproteins Research
- Biochemical and Molecular Research
- Genetics and Neurodevelopmental Disorders
- RNA modifications and cancer
- Enzyme Production and Characterization
- Library Collection Development and Digital Resources
- Infant Nutrition and Health
- Studies on Chitinases and Chitosanases
- Library Science and Information Systems
- Erythrocyte Function and Pathophysiology
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Cancer-related gene regulation
- Photodynamic Therapy Research Studies
- Iron Metabolism and Disorders
- Biomedical Research and Pathophysiology
- Hemoglobinopathies and Related Disorders
Icahn School of Medicine at Mount Sinai
2009-2020
Mount Sinai Medical Center
1987-2015
New York University
2004-2010
University of Wales
1987-2003
University of Pavia
1999-2002
Istituti di Ricovero e Cura a Carattere Scientifico
2000-2002
Western Infirmary
1999-2000
Philipps University of Marburg
2000
Monklands Hospital
1995
National Health Service
1995
FABRY'S DISEASE is an X-linked recessive disorder resulting from deficient activity of the lysosomal hydrolase α-galactosidase A.1-3 The enzymatic defect leads to progressive accumulation neutral glycosphingolipids with terminal α-galactosyl moieties (particularly globotriaosylceramide) in lysosomes vascular endothelial and smooth-muscle cells throughout body. In classically affected males, who have no detectable A activity, onset disease manifestations occurs childhood or adolescence...
The complete nucleotide sequence has been determined for a lambda gt11 cDNA clone (lambda AG18) containing the full-length coding region mature lysosomal form of human alpha-galactosidase A (alpha-Gal A; EC 3.2.1.22). AG18 insert contained 1226-base-pair with an open reading frame encoding 398 amino acids polypeptide (predicted Mr = 45,356) and last 5 propeptide sequence. poly(A) signals AATACA ATTAAA occurred 28 11 nucleotides prior to TAA stop codon, respectively. There was no 3'...
Human alpha-galactosidase A (alpha-D-galactoside galactohydrolase; EC 3.2.1.22) is a lysosomal hydrolase encoded by gene localized to the chromosomal region Xq22. The deficient activity of this enzyme results in Fabry disease, an X chromosome-linked recessive disorder that leads premature death affected males. For studies structure and function for characterization genetic lesions families with full-length cDNA was isolated, sequenced, used screen human genomic libraries. 1393-base-pair had...
Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from the deficient activity lysosomal hydrolase, alpha-galactosidase. Southern hybridization analysis alpha-galactosidase gene in affected hemizygous males 130 unrelated families with disease revealed six different rearrangements and one exonic point mutation resulting obliteration Msp I restriction site. Five partial deletions were detected ranging size 0.4 to greater than 5.5 kb. Four these had...
Recently, the human gene encoding erythroid-specific delta-aminolevulinate synthase was localized to chromosomal region Xp21-Xq21, identifying this as logical candidate for enzymatic defect causing "X-linked" sideroblastic anemia. To investigate hypothesis, 11 exonic coding regions of were amplified and sequenced from a 30-year-old Chinese male with pyridoxine-responsive form X-linked A single T----A transition found in codon 471 highly conserved exon 9, resulting an Ile----Asn substitution....
Human lysosomal alpha-galactosidase A (alpha-Gal A) was stably overexpressed in CHO cells and its biosynthesis targeting were investigated. Clone AGA5.3-1000Mx, which the highest enzyme overexpressor, produced intracellular alpha-Gal levels of 20,900 U/mg (approximately 100 micrograms enzyme/10(7) cells) secreted approximately 13,000 U (or 75 micrograms/10(7) per day. Ultrastructural examination these revealed numerous 0.25-1.5 microns crystalline structures dilated trans-Golgi network (TGN)...
Fabry disease, an inborn error of glycosphingolipid catabolism, results from mutations in the X-linked gene encoding lysosomal enzyme, alpha-galactosidase A (EC 3.2.1.22). Six rearrangements that cause disease were investigated to assess role Alu repetitive elements and short direct and/or inverted repeats generation these germinal mutations. The breakpoints five partial deletions one duplication determined by either cloning sequencing mutant affected hemizygote, or polymerase chain reaction...
Two cDNAs encoding human delta-aminolevulinate dehydratase (ALA-D; porphobilinogen synthase; EC 4.2.1.24), the second enzyme in heme biosynthetic pathway, were identified, recloned into bacteriophage M13, and sequenced by primer extension. The first clone with an 827-base-pair (bp) pEX-ALA-D cDNA insert, shown to contain DNA sequences that colinear four bovine ALA-D peptide sequences, was used screen a pKT218 liver library. A containing 1200-bp insert identified contained open reading frame...
AMONG the inherited neurologic diseases, neuroaxonal dystrophies constitute a group of neurodegenerative disorders characterized by common axonal lesion.1 These include infantile (Seitelberger's disease), late-infantile, and juvenile forms dystrophy, leukodystrophy, Hallervorden–Spatz syndrome, which can be juvenile, or adult onset. The morphologic hallmark these is presence swellings, "spheroids," in terminal endings distal portions axons central nervous system, both. Ultrastructurally,...
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Abstract Erythropoietic protoporphyria (EPP) and X-linked (XLP) are inborn errors of heme biosynthesis with the same phenotype but resulting from autosomal recessive loss-of-function mutations in ferrochelatase ( FECH ) gene gain-of-function erythroid-specific 5-aminolevulinate synthase ALAS2 gene, respectively. The EPP is characterized by acute, painful, cutaneous photosensitivity elevated erythrocyte protoporphyrin levels. We report 155 unrelated North American patients phenotype....
X-linked sideroblastic anemia (XLSA) is caused by muta- tions of the erythroid-specific 6-aminolevulinate synthase gene (ALAS2) resulting in deficient heme synthesis.The characteristic hypochromic, microcytic typically be- comes manifest first three decades life.Hematologic response to pyridoxine variable and rarely complete.We report two unrelated cases highly pyridoxine-responsive XLSA geriatric patients previously diagnosed with refractory ringed sideroblasts.A unaf- fected 77-yr-old male...
ALAD is a zinc metalloenzyme whose inhibition by lead the first and most sensitive indicator of exposure decreased activity has been implicated in pathogenesis poisoning. This heme biosynthetic enzyme encoded gene located at chromosome 9q34, which two codominant alleles, ALAD1 ALAD2. The occurrence frequent alleles for stimulated an investigation into possible pharmacogenetic role polymorphism In New York City population high risk exposure, individuals heterozygous or homozygous less common...
<h3>Background</h3> Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity,is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed have homozygous dominant AIP (HD-AIP) been described (hydroxymethylbilane genotypes R167Q/R167Q and R167W/R173Q). <h3>Objective</h3> investigate the genetic, biochemical, clinical, neuroradiologic features of a severely affected infant with HD-AIP....
Uroporphyrinogen III synthase [URO-synthase; hydroxymethylbilane hydro-lyase (cyclizing), EC 4.2.1.75], the fourth enzyme in heme biosynthetic pathway, is responsible for conversion of linear tetrapyrrole, hydroxymethylbilane, to cyclic uroporphyrinogen III. The deficient activity URO-synthase enzymatic defect autosomal recessive disorder congenital erythropoietic porphyria. To facilitate isolation a full-length cDNA human URO-synthase, erythrocyte was purified homogeneity and 81...
A pilot trial of enzyme replacement with splenic and plasma alpha-galactosidase (alpha-D-galactosidase; alpha-D-galactoside galactohydrolase, EC 3.2.1.22) isozymes was undertaken in two brothers Fabry disease, an X-linked glycosphingolipid storage disease. Six unentrapped doses (2000 units/kg) each isozyme were administered intravenously to the respective recipients during a 117-day period. The circulating half-life about 10 min, whereas that for approximately 70 min. No immune response...
The synthesis and processing of the human lysosomal enzyme a-galactosidase A was examined in normal Fabry fibroblasts.In cells, synthesized as an M, = 50,500 precursor, which contained phosphate groups oligosaccharide chains cleavable by endoglucosaminidase H.The precursor processed via ill-defined intermediates to a mature 46,000 form.Processing complete within 3-7 days after synthesis.In presence NH&l I-cell fibroblasts, majority newly agalactosidase secreted 52,000 form.For comparison,...
Congenital erythropoietic porphyria, an autosomal recessive inborn error of heme biosynthesis, results from the markedly deficient activity uroporphyrinogen III synthase. Extensive mutation analyses 40 unrelated patients only identified approximately 90% mutant alleles. Sequencing recently discovered erythroid-specific promoter in six with a single undefined allele four novel mutations clustered 20-bp region: (a) –70T to C transition putative GATA-1 consensus binding element, (b) –76G A...