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Janos Zempleni - One of the best experts on this subject based on the ideXlab platform.
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Susceptibility to Heat Stress and Aberrant Gene Expression Patterns in Holocarboxylase Synthetase-Deficient Drosophila melanogaster Are Caused by Decreased Biotinylation of Histones, Not of Carboxylases
The Journal of Nutrition, 2018Co-Authors: Gabriela Camporeale, Janos Zempleni, Joel C. EissenbergAbstract:Previously, we discovered that Holocarboxylase Synthetase (HCS) is a chromatin-associated protein in Drosophila melanogaster and that HCS deficiency alters chromatin structure and gene expression patterns, leading to decreased heat tolerance. The effects of HCS deficiency were attributed to decreased biotinylation of histones. However, HCS is known to mediate biotinylation of carboxylases in cytoplasm and mitochondria in addition to mediating biotinylation of histones. A challenge posed by the genetic analysis of HCS is to distinguish between the effects of decreased biotinylation of carboxylases from the effects of decreased histone biotinylation in the gene expression patterns and phenotypes observed in HCS-deficient flies. Here, we tested whether 3-methylcrotonyl-CoA carboxylase (MCC) mutant flies exhibit gene expression patterns and heat susceptibility similar to that in HCS-deficient Drosophila. Biotin transporter [sodium-dependent multivitamin transporter (SMVT)] mutants were used to investigate effects of cellular biotin depletion on gene expression and heat susceptibility. Deficiencies of MCC and SMVT in mutant flies were confirmed by real-time PCR, streptavidin blotting of Holocarboxylases, and analysis of MCC activities; expression of HCS and biotinylation of histones were not altered in MCC and SMVT mutants. Gene expression patterns in MCC and SMVT mutants were different from that seen with HCS-deficient flies, as judged by the abundance of mRNA coding for defective chorion 1, chitin-binding peritrophin-A, dopamine receptor 2, and yolk protein 2. MCC mutants exhibited increased resistance to heat stress compared with wild-type flies. We conclude that gene expression patterns and phenotypes in HCS-deficient flies in previous studies are caused by decreased biotinylation of histones rather than MCC.
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resveratrol compounds inhibit human Holocarboxylase Synthetase and cause a lean phenotype in drosophila melanogaster
Journal of Nutritional Biochemistry, 2015Co-Authors: Elizabeth L Cordonier, Daniel Camara Teixeira, Simone Onur, Richard Zbasnik, Frank Doring, Vicki Schlegel, Riem Adjam, Paul E Read, Janos ZempleniAbstract:Holocarboxylase Synthetase (HLCS) is the sole protein-biotin ligase in the human proteome. HLCS has key regulatory functions in intermediary metabolism, including fatty acid metabolism, and in gene repression through epigenetic mechanisms. The objective of this study was to identify food-borne inhibitors of HLCS that alter HLCS-dependent pathways in metabolism and gene regulation. When libraries of extracts from natural products and chemically pure compounds were screened for HLCS inhibitor activity, resveratrol compounds in grape materials caused an HLCS inhibition of >98% in vitro. The potency of these compounds was piceatannol>resveratrol>piceid. Grape-borne compounds other than resveratrol metabolites also contributed toward HLCS inhibition, e.g., p-coumaric acid and cyanidin chloride. HLCS inhibitors had meaningful effects on body fat mass. When Drosophila melanogaster brummer mutants, which are genetically predisposed to storing excess amounts of lipids, were fed diets enriched with grape leaf extracts and piceid, body fat mass decreased by more than 30% in males and females. However, Drosophila responded to inhibitor treatment with an increase in the expression of HLCS, which elicited an increase in the abundance of biotinylated carboxylases in vivo. We conclude that mechanisms other than inhibition of HLCS cause body fat loss in flies. We propose that the primary candidate is the inhibition of the insulin receptor/Akt signaling pathway.
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β keto and β hydroxyphosphonate analogs of biotin 5 amp are inhibitors of Holocarboxylase Synthetase
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Wantanee Sittiwong, Janos Zempleni, Elizabeth L Cordonier, Patrick H DussaultAbstract:Abstract Holocarboxylase Synthetase (HLCS) catalyzes the covalent attachment of biotin to cytoplasmic and mitochondrial carboxylases, nuclear histones, and over a hundred human proteins. Nonhydrolyzable ketophosphonate (β-ketoP) and hydroxyphosphonate (β-hydroxyP) analogs of biotin-5′-AMP inhibit Holocarboxylase Synthetase (HLCS) with IC 50 values of 39.7 μM and 203.7 μM. By comparison, an IC 50 value of 7 μM was observed with the previously reported biotinol-5′-AMP. The K i values, 3.4 μM and 17.3 μM, respectively, are consistent with the IC 50 results, and close to the K i obtained for biotinol-5′-AMP (7 μM). The β-ketoP and β-hydroxyP molecules are competitive inhibitors of HLCS while biotinol-5′-AMP inhibited HLCS by a mixed mechanism.
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Holocarboxylase Synthetase interacts physically with nuclear receptor co repressor histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats
Biochemical Journal, 2014Co-Authors: Dandan Liu, Janos ZempleniAbstract:HLCS (Holocarboxylase Synthetase) is a nuclear protein that catalyses the binding of biotin to distinct lysine residues in chromatin proteins. HLCS-dependent epigenetic marks are over-represented in repressed genomic loci, particularly in repeats. Evidence is mounting that HLCS is a member of a multi-protein gene repression complex, which determines its localization in chromatin. In the present study we tested the hypothesis that HLCS interacts physically with N-CoR (nuclear receptor co-repressor) and HDAC1 (histone deacetylase 1), thereby contributing toward the removal of H3K9ac (Lys9-acetylated histone H3) gene activation marks and the repression of repeats. Physical interactions between HLCS and N-CoR, HDAC1 and a novel splicing variant of HDAC1 were confirmed by co-immunoprecipitation, limited proteolysis and split luciferase complementation assays. When HLCS was overexpressed, the abundance of H3K9ac marks decreased by 50% and 68% in LTRs (long terminal repeats) 15 and 22 respectively in HEK (human embryonic kidney)-293 cells compared with the controls. This loss of H3K9ac marks was linked with an 83% decrease in mRNA coding for LTRs. Similar patterns were seen in pericentromeric alpha satellite repeats in chromosomes 1 and 4. We conclude that interactions of HLCS with N-CoR and HDACs contribute towards the transcriptional repression of repeats, presumably increasing genome stability. Abbreviations: CDK3, cyclin-dependent kinase 3; DNMT1, DNA methyltransferase 1; EHMT-1, euchromatic histone-lysine N-methyltransferase-1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GST, glutathione transferase; HA, haemagglutinin; HDAC, histone deacetylase; HEK, human embryonic kidney; H3K9ac, Lys9-acetylated histone H3; H3K9me, Lys9-methylated histone H3; HLCS, Holocarboxylase Synthetase; LTR, long terminal repeat; MBP-1, c-Myc promoter-binding protein-1; MDM2, murine double minute 2; MeCP2, methyl CpG-binding protein 2; N-CoR, nuclear receptor co-repressor; qPCR, quantitative real-time PCR; TP53, tumour protein p53
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novel roles of Holocarboxylase Synthetase in gene regulation and intermediary metabolism
Nutrition Reviews, 2014Co-Authors: Janos Zempleni, Dandan Liu, Daniel Teixeira Camara, Elizabeth L CordonierAbstract:The role of Holocarboxylase Synthetase (HLCS) in catalyzing the covalent binding of biotin to the five biotin-dependent carboxylases in humans is well established, as are the essential roles of these carboxylases in the metabolism of fatty acids, the catabolism of leucine, and gluconeogenesis. This review examines recent discoveries regarding the roles of HLCS in assembling a multiprotein gene repression complex in chromatin. In addition, emerging evidence suggests that the number of biotinylated proteins is far larger than previously assumed and includes members of the heat-shock superfamily of proteins and proteins coded by the ENO1 gene. Evidence is presented linking biotinylation of heat-shock proteins HSP60 and HSP72 with redox biology and immune function, respectively, and biotinylation of the two ENO1 gene products MBP-1 and ENO1 with tumor suppression and glycolysis, respectively.
Kuniaki Narisawa - One of the best experts on this subject based on the ideXlab platform.
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haplotype analysis suggests that the two predominant mutations in japanese patients with Holocarboxylase Synthetase deficiency are founder mutations
Journal of Human Genetics, 2000Co-Authors: Xue Yang, Yoko Aoki, Kuniaki Narisawa, Osamu Sakamoto, Masahiro Hiratsuka, Kenneth Michael Gibson, Yoichi Matsubara, Shigeo Kure, Yoichi SuzukiAbstract:Holocarboxylase Synthetase (HCS) deficiency is a rare autosomal recessive disorder of biotin metabolism. Including three new Japanese patients we diagnosed in this study, ten Japanese families have, so far, been accumulated. In these families, the mutations 237Leu > Pro (sevenalleles) and 1067delG (five alleles) were predominant; 508Arg > Trp and 550Val > Met mutations were identified in three families in the heterozygous form and in one patient in the homozygous form, respectively. To determine the origin of these mutations, we identified new polymorphic microsatellite markers in the HCS gene and analyzed the haplotypes of the patients. All the 237Leu > Pro and the 1067delG alleles were associated with haplotype 2-2. This finding is consistent with the notion that these mutations are founder mutations in the Japanese population. Three Japanese 508Arg > Trp alleles were associated with several haplotypes, including 2-3 and 1-4. The haplotype of a Taiwanese patient homozygous for the 508Arg > Trp mutation was 2-3/2-3. The haplotype of one Japanese patient homozygous for the 550Val > Met mutation was 1-4/1-4, whereas that of a Jewish patient with the same homozygous mutation was 2-3/2-3. Both mutations were associated with at least two haplotypes and were found in several ethnic groups. The changes 508Arg > Trp and 550Val > Met occurred at CpG dinucleotide. The data suggest that these two mutations represent a mutational hot-spot.
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late onset Holocarboxylase Synthetase deficiency with homologous r508w mutation
Journal of the Formosan Medical Association, 2000Co-Authors: Wuhliang Hwu, Yoichi Suzuki, Kuniaki Narisawa, Xue Yang, Shi Ping Chou, Wenyu TsaiAbstract:Holocarboxylase Synthetase (HCS) is responsible for the biotinylation of pyruvate carboxylase, propionyl coenzyme A (CoA) carboxylase, beta-methylcrotonoyl CoA carboxylase, and acetyl CoA carboxylase. We report on a patient with HCS deficiency resulting in a rare metabolic disease. The patient, a 2-year-old boy, presented with vomiting, consciousness disturbance, and dyspnea. Laboratory examinations showed hyperglycemia, hyperammonemia, lactic acidosis, and excretion of large amounts of beta-hydroxyisovalerate and beta-methylcrotonylglycine in the urine. After 10 days of treatment with biotin 5 mg.kg-1.day-1, the abnormal organic acids in his urine had almost completely disappeared. There were no subsequent attacks, and his growth and development remained normal during 1 year of follow-up. Nucleotide sequence analysis of the HCS cDNA of the patient revealed a homozygous 1809C-->T (R508W) mutation. The R508W mutation is found worldwide, and might be associated with higher residual HCS activity than other mutations. Late-onset HCS deficiency cannot be differentiated clinically from biotinidase deficiency. Prompt and correct diagnosis is important for these biotin-responsive disorders.
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diagnosis and molecular analysis of an atypical case of Holocarboxylase Synthetase deficiency
European Journal of Pediatrics, 2000Co-Authors: Osamu Sakamoto, Yoichi Suzuki, Yoko Aoki, Masahiro Hiratsuka, Elisabeth Holme, Jun Kudoh, Nobuyoshi Shimizu, Kuniaki NarisawaAbstract:Holocarboxylase Synthetase (HCS) deficiency is a disorder of biotin metabolism characterised by metabolic ketoacidosis and skin lesions due to reduced activities of multiple biotin-dependent carboxylases. The onset of this disease is usually between the neonatal and infantile period. Here we report the molecular analysis of an atypical case of HCS deficiency, where the patient developed his first episode of acidosis at age 8 years and had an exceptionally slow response to biotin therapy. A homozygous mutation was identified at the +5 position of the splice donor site in intron 10 of the HCS gene (IVs10 + 5(g → a)), resulting in abnormal splicing of HCS mRNA. A moderate decrease in the amount of normal HCS mRNA may account for the atypical, late-onset phenotype of this patient.
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Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in Holocarboxylase Synthetase deficiency.
Pediatric Research, 1999Co-Authors: Osamu Sakamoto, Yoichi Suzuki, Yoko Aoki, Xue Li, Masahiro Hiratsuka, Terttu Suormala, E R Baumgartner, Kenneth Michael Gibson, Kuniaki NarisawaAbstract:Relationship between Kinetic Properties of Mutant Enzyme and Biochemical and Clinical Responsiveness to Biotin in Holocarboxylase Synthetase Deficiency
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identification and characterization of mutations in patients with Holocarboxylase Synthetase deficiency
Human Genetics, 1999Co-Authors: Yoko Aoki, Yoichi Suzuki, Paz Briones, Regula E Baumgartner, Osamu Sakamoto, Masahiro Hiratsuka, Terttu Suormala, Hiroshi Akaishi, Kuniaki NarisawaAbstract:Holocarboxylase Synthetase deficiency (HCS) is an autosomal recessive disorder characterized by metabolic ketoacidosis, abnormal urine organic metabolites, and dermatitis. These symptoms are improved by pharmacological doses of biotin. In this study, we have analyzed seven patients with HCS deficiency found in European and Middle Eastern countries by using reverse transcription/polymerase chain reaction/single-stranded conformation polymorphism and a sequencing analysis. Although we had previously reported that two mutations were frequent in Japanese patients, no frequent mutations were found in the patients analyzed in this study. Seven novel mutations were identified in the cDNA of the patients; these included three missense mutations, two single-base deletions that resulted in a termination codon, a three-base in-frame deletion, and a 68-bp deletion. A new polymorphism C1121T was also identified in four alleles. A transient expression study demonstrated that the HCS activities of three missense mutations and one amino acid deletion were 1%–14% that of wild-type cDNA; in contrast, the activities of the two single-base deletions followed by a termination codon and Asp571Asn were nearly undetectable. These data suggest that a variety of mutations is responsible for decreasing HCS activity and that the aspartate residue at amino acid position 571 may be crucial for the catalytic activity of HCS.
Yoko Aoki - One of the best experts on this subject based on the ideXlab platform.
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mutations in the Holocarboxylase Synthetase gene hlcs
Human Mutation, 2005Co-Authors: Yoichi Suzuki, Yoko Aoki, Xue Yang, Shigeo Kure, Yoichi MatsubaraAbstract:Holocarboxylase Synthetase (HLCS) deficiency is an autosomal recessive disorder. HLCS is an enzyme that catalyzes biotin incorporation into carboxylases and histones. Since the first report of the cDNA sequence, 30 mutations in the HLCS gene have been reported. Mutations occur throughout the entire coding region except exons 6 and 10. The types of mutations are one single amino acid deletion, five single nucleotide insertions/deletions, 22 missense mutations, and two nonsense mutations. The only intronic mutation identified thus far is c.1519+5G>A (also designated IVS10+5G>A), which causes a splice error. Several lines of evidence suggest that c.1519+5G>A is a founder mutation in Scandinavian patients. Prevalence of this mutation is about 10 times higher in the Faroe Islands than in the rest of the world. The mutations p.L237P and c.780delG are predominant only in Japanese patients. These are probably founder mutations in this population. Mutations p.R508W and p.V550M are identified in several ethic groups and accompanied with various haplotypes, suggesting that these are recurrent mutations. There is a good relationship between clinical biotin responsiveness and the residual activity of HLCS. A combination of a null mutation and a point mutation that shows less than a few percent of the normal activity results in neonatal onset. Patients who have mutant HLCS with higher residual activity develop symptom after the neonatal period and show a good clinical response to biotin therapy.
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partial response to biotin therapy in a patient with Holocarboxylase Synthetase deficiency clinical biochemical and molecular genetic aspects
Molecular Genetics and Metabolism, 2003Co-Authors: Rene Santer, Yoichi Suzuki, Yoko Aoki, Terttu Suormala, E R Baumgartner, Xue Yang, M Duran, Hiltrud Muhle, Ulrich StephaniAbstract:Abstract We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset Holocarboxylase Synthetase (HCS, gene symbol HLCS ) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 +5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype–phenotype correlation that unequivocally exists in HCS deficiency.
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structure of human Holocarboxylase Synthetase gene and mutation spectrum of Holocarboxylase Synthetase deficiency
Human Genetics, 2001Co-Authors: Xue Yang, Yoko Aoki, Osamu Sakamoto, Masahiro Hiratsuka, Shigeo Kure, Sepidh Taheri, E Christensen, Koji Inui, Mitsuru Kubota, Miki OhiraAbstract:Holocarboxylase Synthetase (HLCS) is an enzyme that catalyzes the incorporation of biotin into apo-carboxylases, and its deficiency causes biotin-responsive multiple carboxylase deficiency. The reported sequences of cDNA for human HLCS from liver, lymphocyte, and KG-1 myeloid cell lines differ at their 5′ regions. To elucidate variations of the human HLCS mRNA and longer 5′ cDNA ends, we performed screening of the human liver cDNA library and rapid amplification of the cDNA ends (RACE). Our results suggest the existence of three types of HLCS mRNA that start at different exons. The first type starts at exon 1, and the second type starts at exon 3, and both are found in various human tissues. The third type, corresponding to the cDNA from the KG-1 cell, starts at exon 2 of the HLCS gene. Various splicing patterns from exons 3–6 were also observed. None of the variations of cDNA found created a new initiation codon. Mutation screening from exons 6–14, therefore, was sufficient to detect amino acid changes in HLCS in patients. Our direct sequencing strategy for screening mutations in the HLCS gene revealed mutations in five Japanese patients and seven non-Japanese patients. Our analyses involving 12 Japanese and 13 non-Japanese patients and studies by others indicate that (1) there is no panethnically prevalent mutation; (2) the Arg508Trp, Gly581Ser, and Val550Met mutations are found in both Japanese and non-Japanese populations; (3) the IVS10+5G→A mutation is predominant and probably a founder mutation in European patients; (4) the 655–656insA, Leu237Pro, and 780delG mutations are unique in Japanese patients; (5) the spectrum of the mutations in the HLCS gene may vary substantially among different ethnic groups.
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haplotype analysis suggests that the two predominant mutations in japanese patients with Holocarboxylase Synthetase deficiency are founder mutations
Journal of Human Genetics, 2000Co-Authors: Xue Yang, Yoko Aoki, Kuniaki Narisawa, Osamu Sakamoto, Masahiro Hiratsuka, Kenneth Michael Gibson, Yoichi Matsubara, Shigeo Kure, Yoichi SuzukiAbstract:Holocarboxylase Synthetase (HCS) deficiency is a rare autosomal recessive disorder of biotin metabolism. Including three new Japanese patients we diagnosed in this study, ten Japanese families have, so far, been accumulated. In these families, the mutations 237Leu > Pro (sevenalleles) and 1067delG (five alleles) were predominant; 508Arg > Trp and 550Val > Met mutations were identified in three families in the heterozygous form and in one patient in the homozygous form, respectively. To determine the origin of these mutations, we identified new polymorphic microsatellite markers in the HCS gene and analyzed the haplotypes of the patients. All the 237Leu > Pro and the 1067delG alleles were associated with haplotype 2-2. This finding is consistent with the notion that these mutations are founder mutations in the Japanese population. Three Japanese 508Arg > Trp alleles were associated with several haplotypes, including 2-3 and 1-4. The haplotype of a Taiwanese patient homozygous for the 508Arg > Trp mutation was 2-3/2-3. The haplotype of one Japanese patient homozygous for the 550Val > Met mutation was 1-4/1-4, whereas that of a Jewish patient with the same homozygous mutation was 2-3/2-3. Both mutations were associated with at least two haplotypes and were found in several ethnic groups. The changes 508Arg > Trp and 550Val > Met occurred at CpG dinucleotide. The data suggest that these two mutations represent a mutational hot-spot.
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diagnosis and molecular analysis of an atypical case of Holocarboxylase Synthetase deficiency
European Journal of Pediatrics, 2000Co-Authors: Osamu Sakamoto, Yoichi Suzuki, Yoko Aoki, Masahiro Hiratsuka, Elisabeth Holme, Jun Kudoh, Nobuyoshi Shimizu, Kuniaki NarisawaAbstract:Holocarboxylase Synthetase (HCS) deficiency is a disorder of biotin metabolism characterised by metabolic ketoacidosis and skin lesions due to reduced activities of multiple biotin-dependent carboxylases. The onset of this disease is usually between the neonatal and infantile period. Here we report the molecular analysis of an atypical case of HCS deficiency, where the patient developed his first episode of acidosis at age 8 years and had an exceptionally slow response to biotin therapy. A homozygous mutation was identified at the +5 position of the splice donor site in intron 10 of the HCS gene (IVs10 + 5(g → a)), resulting in abnormal splicing of HCS mRNA. A moderate decrease in the amount of normal HCS mRNA may account for the atypical, late-onset phenotype of this patient.
Yoichi Suzuki - One of the best experts on this subject based on the ideXlab platform.
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mutations in the Holocarboxylase Synthetase gene hlcs
Human Mutation, 2005Co-Authors: Yoichi Suzuki, Yoko Aoki, Xue Yang, Shigeo Kure, Yoichi MatsubaraAbstract:Holocarboxylase Synthetase (HLCS) deficiency is an autosomal recessive disorder. HLCS is an enzyme that catalyzes biotin incorporation into carboxylases and histones. Since the first report of the cDNA sequence, 30 mutations in the HLCS gene have been reported. Mutations occur throughout the entire coding region except exons 6 and 10. The types of mutations are one single amino acid deletion, five single nucleotide insertions/deletions, 22 missense mutations, and two nonsense mutations. The only intronic mutation identified thus far is c.1519+5G>A (also designated IVS10+5G>A), which causes a splice error. Several lines of evidence suggest that c.1519+5G>A is a founder mutation in Scandinavian patients. Prevalence of this mutation is about 10 times higher in the Faroe Islands than in the rest of the world. The mutations p.L237P and c.780delG are predominant only in Japanese patients. These are probably founder mutations in this population. Mutations p.R508W and p.V550M are identified in several ethic groups and accompanied with various haplotypes, suggesting that these are recurrent mutations. There is a good relationship between clinical biotin responsiveness and the residual activity of HLCS. A combination of a null mutation and a point mutation that shows less than a few percent of the normal activity results in neonatal onset. Patients who have mutant HLCS with higher residual activity develop symptom after the neonatal period and show a good clinical response to biotin therapy.
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partial response to biotin therapy in a patient with Holocarboxylase Synthetase deficiency clinical biochemical and molecular genetic aspects
Molecular Genetics and Metabolism, 2003Co-Authors: Rene Santer, Yoichi Suzuki, Yoko Aoki, Terttu Suormala, E R Baumgartner, Xue Yang, M Duran, Hiltrud Muhle, Ulrich StephaniAbstract:Abstract We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset Holocarboxylase Synthetase (HCS, gene symbol HLCS ) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 +5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype–phenotype correlation that unequivocally exists in HCS deficiency.
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haplotype analysis suggests that the two predominant mutations in japanese patients with Holocarboxylase Synthetase deficiency are founder mutations
Journal of Human Genetics, 2000Co-Authors: Xue Yang, Yoko Aoki, Kuniaki Narisawa, Osamu Sakamoto, Masahiro Hiratsuka, Kenneth Michael Gibson, Yoichi Matsubara, Shigeo Kure, Yoichi SuzukiAbstract:Holocarboxylase Synthetase (HCS) deficiency is a rare autosomal recessive disorder of biotin metabolism. Including three new Japanese patients we diagnosed in this study, ten Japanese families have, so far, been accumulated. In these families, the mutations 237Leu > Pro (sevenalleles) and 1067delG (five alleles) were predominant; 508Arg > Trp and 550Val > Met mutations were identified in three families in the heterozygous form and in one patient in the homozygous form, respectively. To determine the origin of these mutations, we identified new polymorphic microsatellite markers in the HCS gene and analyzed the haplotypes of the patients. All the 237Leu > Pro and the 1067delG alleles were associated with haplotype 2-2. This finding is consistent with the notion that these mutations are founder mutations in the Japanese population. Three Japanese 508Arg > Trp alleles were associated with several haplotypes, including 2-3 and 1-4. The haplotype of a Taiwanese patient homozygous for the 508Arg > Trp mutation was 2-3/2-3. The haplotype of one Japanese patient homozygous for the 550Val > Met mutation was 1-4/1-4, whereas that of a Jewish patient with the same homozygous mutation was 2-3/2-3. Both mutations were associated with at least two haplotypes and were found in several ethnic groups. The changes 508Arg > Trp and 550Val > Met occurred at CpG dinucleotide. The data suggest that these two mutations represent a mutational hot-spot.
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late onset Holocarboxylase Synthetase deficiency with homologous r508w mutation
Journal of the Formosan Medical Association, 2000Co-Authors: Wuhliang Hwu, Yoichi Suzuki, Kuniaki Narisawa, Xue Yang, Shi Ping Chou, Wenyu TsaiAbstract:Holocarboxylase Synthetase (HCS) is responsible for the biotinylation of pyruvate carboxylase, propionyl coenzyme A (CoA) carboxylase, beta-methylcrotonoyl CoA carboxylase, and acetyl CoA carboxylase. We report on a patient with HCS deficiency resulting in a rare metabolic disease. The patient, a 2-year-old boy, presented with vomiting, consciousness disturbance, and dyspnea. Laboratory examinations showed hyperglycemia, hyperammonemia, lactic acidosis, and excretion of large amounts of beta-hydroxyisovalerate and beta-methylcrotonylglycine in the urine. After 10 days of treatment with biotin 5 mg.kg-1.day-1, the abnormal organic acids in his urine had almost completely disappeared. There were no subsequent attacks, and his growth and development remained normal during 1 year of follow-up. Nucleotide sequence analysis of the HCS cDNA of the patient revealed a homozygous 1809C-->T (R508W) mutation. The R508W mutation is found worldwide, and might be associated with higher residual HCS activity than other mutations. Late-onset HCS deficiency cannot be differentiated clinically from biotinidase deficiency. Prompt and correct diagnosis is important for these biotin-responsive disorders.
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diagnosis and molecular analysis of an atypical case of Holocarboxylase Synthetase deficiency
European Journal of Pediatrics, 2000Co-Authors: Osamu Sakamoto, Yoichi Suzuki, Yoko Aoki, Masahiro Hiratsuka, Elisabeth Holme, Jun Kudoh, Nobuyoshi Shimizu, Kuniaki NarisawaAbstract:Holocarboxylase Synthetase (HCS) deficiency is a disorder of biotin metabolism characterised by metabolic ketoacidosis and skin lesions due to reduced activities of multiple biotin-dependent carboxylases. The onset of this disease is usually between the neonatal and infantile period. Here we report the molecular analysis of an atypical case of HCS deficiency, where the patient developed his first episode of acidosis at age 8 years and had an exceptionally slow response to biotin therapy. A homozygous mutation was identified at the +5 position of the splice donor site in intron 10 of the HCS gene (IVs10 + 5(g → a)), resulting in abnormal splicing of HCS mRNA. A moderate decrease in the amount of normal HCS mRNA may account for the atypical, late-onset phenotype of this patient.
E R Baumgartner - One of the best experts on this subject based on the ideXlab platform.
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partial response to biotin therapy in a patient with Holocarboxylase Synthetase deficiency clinical biochemical and molecular genetic aspects
Molecular Genetics and Metabolism, 2003Co-Authors: Rene Santer, Yoichi Suzuki, Yoko Aoki, Terttu Suormala, E R Baumgartner, Xue Yang, M Duran, Hiltrud Muhle, Ulrich StephaniAbstract:Abstract We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset Holocarboxylase Synthetase (HCS, gene symbol HLCS ) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 +5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype–phenotype correlation that unequivocally exists in HCS deficiency.
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Relationship between kinetic properties of mutant enzyme and biochemical and clinical responsiveness to biotin in Holocarboxylase Synthetase deficiency.
Pediatric Research, 1999Co-Authors: Osamu Sakamoto, Yoichi Suzuki, Yoko Aoki, Xue Li, Masahiro Hiratsuka, Terttu Suormala, E R Baumgartner, Kenneth Michael Gibson, Kuniaki NarisawaAbstract:Relationship between Kinetic Properties of Mutant Enzyme and Biochemical and Clinical Responsiveness to Biotin in Holocarboxylase Synthetase Deficiency
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Holocarboxylase Synthetase deficiency: Report of a case with onset in late infancy
Journal of Inherited Metabolic Disease, 1999Co-Authors: E. Touma, E R Baumgartner, T. Suormala, B. Gerbaka, H. Ogier De Baulny, J. LoiseletAbstract:A case of Holocarboxylase Synthetase (HCS) deficiency of late-infantile onset is presented and compared with the common manifestations in previously reported patients. Our patient had her first episode at 20 months followed by recurrent episodes of metabolic acidosis with ketolactic acidosis responding dramatically to a short trial of biotin and thiamin. The main clinical findings were metabolic acidosis with alteration in consciousness and respiration, which are in accordance with findings in earlier reported patients with both neonatal-onset and infantile-onset forms of HCS deficiency. The diagnosis of HCS deficiency was made only at the age of 5.5 years during a metabolic work-up when organic acid analysis was performed. This revealed elevated urinary excretion of the characteristic metabolites, 3-hydroxypropionate, 3-hydroxyisovalerate and methylcitrate, suggesting multiple carboxylase deficiency (MCD). MCD was demonstrated in fibroblasts of our patient, but only when the cells were grown in a medium with a very low biotin concentration of10^−10mol/L. Kinetic studies of reactivation of deficient propionyl-CoA carboxylase activity with biotin in intact fibroblasts revealed a mildly decreased reactivation rate and only a 3–5 times higher biotin requirement as compared with controls. These findings are in accordance with a mild form of HCS deficiency.This child responded to 10mg/day of biotin with normal lymphocyte carboxylase activities and adequate school performance at 10 years of age.
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late onset Holocarboxylase Synthetase deficiency pre and post natal diagnosis and evaluation of effectiveness of antenatal biotin therapy
European Journal of Pediatrics, 1998Co-Authors: Terttu Suormala, Brian Fowler, C Jakobs, M Duran, W Lehnert, K Raab, H Wick, E R BaumgartnerAbstract:The clinical and biochemical findings in a family with late-onset Holocarboxylase Synthetase (HCS) deficiency are described. The index patient had two life-threatening episodes of metabolic decompensation at the age of 13 and 18 months with ketotic hypoglycaemia, vomiting and progressive loss of consciousness. The child recovered without biotin therapy. Organic aciduria characteristic of multiple carboxylase deficiency (MCD) was found, however, the key metabolites were only slightly elevated in some samples. Biotinidase deficiency was considered but excluded by the finding of normal plasma biotinidase activity. The correct diagnosis was made only at the age of 19 months when severe MCD was found in lymphocytes in the presence of normal plasma biotin concentration. HCS deficiency was confirmed by fibroblast studies. Biotin therapy (20 or 40 mg/day) prevented further episodes and normalized biochemical parameters with so far normal development.
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late onset Holocarboxylase Synthetase deficiency pre and post natal diagnosis and evaluation of effectiveness of antenatal biotin therapy
European Journal of Pediatrics, 1998Co-Authors: Terttu Suormala, Brian Fowler, C Jakobs, M Duran, W Lehnert, K Raab, H Wick, E R BaumgartnerAbstract:The clinical and biochemical findings in a family with late-onset Holocarboxylase Synthetase (HCS) deficiency are described. The index patient had two life-threatening episodes of metabolic decompensation at the age of 13 and 18 months with ketotic hypoglycaemia, vomiting and progressive loss of consciousness. The child recovered without biotin therapy. Organic aciduria characteristic of multiple carboxylase deficiency (MCD) was found, however, the key metabolites were only slightly elevated in some samples. Biotinidase deficiency was considered but excluded by the finding of normal plasma biotinidase activity. The correct diagnosis was made only at the age of 19 months when severe MCD was found in lymphocytes in the presence of normal plasma biotin concentration. HCS deficiency was confirmed by fibroblast studies. Biotin therapy (20 or 40 mg/day) prevented further episodes and normalized biochemical parameters with so far normal development. During two subsequent pregnancies, 10 mg biotin/day was administered to the mother from the 20th week of gestation. At delivery plasma biotin in cord blood samples was 3–4 times higher than in maternal plasma. The 2nd child was unaffected. In the 3rd pregnancy prenatal diagnosis was performed at 16 weeks of gestation. The concentration of methylcitrate in amniotic fluid was within the normal range and that of 3-hydroxyisovalerate only slightly elevated. However, enzyme assays in cultured amniotic fluid cells were consistent with an affected fetus. At birth, carboxylase activities in lymphocytes of this newborn were only moderately decreased to 37% of mean normal. HCS deficiency was confirmed postnatally in fibroblasts. Development remains normal on biotin therapy (20 mg/day). Conclusion Prenatal diagnosis in families with milder forms of HCS deficiency has to be performed by enzyme assays in cultured amniotic cells since organic acid analysis of amniotic fluid may be inconclusive in affected fetuses. Biotin administered prenatally is effectively taken up by the fetus and prevents functional deficiency of the carboxylases in an affected newborn.