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)

We have identified a compound dinucleotide repeat within intron 7 of the human erythroid 5-aminolevulinate synthase (ALAS2) gene with a minimum of 9 alleles and heterozygosity of 78%. ALAS2 was placed on the multipoint linkage map of the X chromosome in the pericentromeric region with the locus order: pter-(DXS255, TFE3, DXS146)-(DXS14, ALAS2, DXZ1)-AR-(DXS153, DXS159)-qter. No recombination was observed between ALAS2 and the centromere marker DXZ1. As ALAS2 has recently been shown to be the defective locus in X-linked pyridoxine-responsive sideroblastic anemia (PRSA), the ALAS2 marker has allowed placement of the gene for PRSA into the multipoint linkage map of the X chromosome. With the previous exclusion of close linkage between DXS14 and sideroblastic anemia with ataxia, our data show that there are at least two loci for X-linked sideroblastic anemia.
Hum Mol Genet 1992 Nov
PMID:Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia. 130 Nov 72

X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder characterized by an infantile to early childhood onset of non-progressive cerebellar ataxia and mild anemia with hypochromia and microcytosis. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to Xq13, a region previously shown by linkage analysis to harbor the XLSA/A gene. This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The full-length ABC7 cDNA was cloned and the entire coding region screened for mutations in a kindred in which five male members manifested XLSA/A. An I400M variant was identified in a predicted transmembrane segment of the ABC7 gene in patients with XLSA/A. The mutation was shown to segregate with the disease in the family and was not detected in at least 600 chromosomes of general population controls. Introduction of the corresponding mutation into the Saccharomyces cerevisiae ATM1 gene resulted in a partial loss of function of the yeast Atm1 protein. In addition, the human wild-type ABC7 protein was able to complement ATM1 deletion in yeast. These data indicate that ABC7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease caused by a mutation in the nuclear genome.
Hum Mol Genet 1999 May
PMID:Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). 1019 63

ATP-binding cassette (ABC) transporter genes are ubiquitously present in most organisms from bacteria to man. This gene family is the largest one known as of yet. Still growing, the number of human ABC transporters counts currently 47 members which belong to seven subfamilies. ABC transporters share a similar molecular architecture: (1) Full-structured transporters harbor two symmetric halves each consisting of one nucleotide binding domain (NBD) and one transmembrane domain (TMD). (2) Half-transporters with one NBD and one TMD homo- or heterodimerize to functional transporter complexes. ABC transporters are "traffic ATPases" which hydrolyze ATP and which transport a wide array of molecules or conduct the transport of molecules by stimulating other translocation mechanisms. Many ABC transporters are involved in human inherited or sporadic diseases such as cystic fibrosis, adrenoleukodystrophy, Stargardt's disease, drug-resistant tumors, Dubin-Johnson syndrome, Byler's disease, progressive familiar intrahepatic cholestasis, X-linked sideroblastic anemia and ataxia, persistent hyperinsulimenic hypoglycemia of infancy, and others. The present review summarizes the current findings in basic research and the efforts for bridging the gap to clinical applications in therapy and diagnostics.
Curr Mol Med 2001 Mar
PMID:The human ATP-binding cassette transporter genes: from the bench to the bedside. 1189 42

5-Aminolevulinate synthase, a pyridoxal 5'-phosphate-dependent enzyme, catalyzes the condensation of glycine with succinyl-coenzyme A to yield aminolevulinate, carbon dioxide and CoA. This reaction corresponds to the first and regulatory step of the mammalian heme biosynthetic pathway. Mutations in the erythroid aminolevulinate synthase gene are associated with X-linked sideroblastic anemia, an erythropoietic disorder characterized by the presence of hypochromic-microcytic erythrocytes in peripheral blood and ring sideroblasts in bone marrow. In the past five years, transient kinetic studies in conjunction with three-dimensional structure models and engineered variants of aminolevulinate synthase have been instrumental in understanding the individual steps of the catalytic mechanism of aminolevulinate synthase. The mechanism of folding, assembly of the two subunits into a functional, dimeric holoenzyme has been recently explored in this laboratory using circular permutation of aminolevulinate synthase.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Circular permutation of 5-aminolevulinate synthase as a tool to evaluate folding, structure and function. 1192 42

Hereditary sideroblastic anemia (HSA) is a heterogeneous group of inherited anemic disorders which is characterized by the presence of ringed sideroblasts in the bone marrow, microcytic hypochromic anemia and typically its X-linked inheritance in patients. It has been shown that a deficiency of the erythroid-specific delta-aminolevulinate synthase (ALAS-E) activity is responsible for pyridoxine-responsive HSA in many patients, however, the pathogenesis of other types of HSA remains still unknown. In this article, recent evidence suggesting multiple causes for HSA is summarized and discussed.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Multiple mechanisms for hereditary sideroblastic anemia. 1192 48

5-Aminolevulinate synthase, a pyridoxal 5'-phosphate-dependent enzyme of the alpha-oxoamine synthase family, catalyzes the first step of the heme biosynthetic pathway in mammalian cells. This reaction entails the condensation of glycine with succinyl-coenzyme A to yield 5-aminolevulinate, carbon dioxide and CoA. Mutations in the erythroid aminolevulinate synthase gene lead to a defective enzyme and are associated with the erythropoietic disorder X-linked sideroblastic anemia. In the past few years, rapid scanning-stopped-flow spectroscopy and chemical quenched-flow studies of the ALAS reaction, under single- and multi-turnover conditions, have provided important results for the interpretation of the catalytic mechanism. In particular, the role of the protein scaffold in modulating the chemical reactivity of the pyridoxal 5'-phosphate cofactor and, thus, the catalytic pathway of ALAS has been investigated in our laboratory using transient kinetics and global analysis of the kinetic data.
Cell Mol Biol (Noisy-le-grand) 2002 Dec
PMID:Mechanism of 5-aminolevulinate synthase and the role of the protein environment in controlling the cofactor chemistry. 1269 40

Proteins with iron-sulfur (Fe-S) clusters participate in multiple metabolic pathways throughout the cell. The mitochondrial ABC half-transporter Abcb7, which is mutated in X-linked sideroblastic anemia with ataxia in humans, is a functional ortholog of yeast Atm1p and is predicted to export a mitochondrially derived metabolite required for cytosolic Fe-S cluster assembly. Using an inducible Cre/loxP system to delete exons 9 and 10 of the Abcb7 gene, we examined the phenotype of mice deficient in Abcb7. We found that Abcb7 was essential in extra-embryonic tissues early in gestation and that the mutant allele exhibits an X-linked parent-of-origin lethality effect. Furthermore, using X-chromosome inactivation assays and tissue-specific deletions, Abcb7 was found to be essential for the development and function of numerous other cell types and tissues. A notable exception to this was liver, where loss of Abcb7 impaired cytosolic Fe-S cluster assembly but was not lethal. In this situation, control of iron regulatory protein 1, a key cytosolic modulator of iron metabolism, which is responsive to the availability of cytosolic Fe-S clusters, was impaired and contributed to the dysregulation of hepatocyte iron metabolism. Altogether, these studies demonstrate the essential nature of Abcb7 in mammals and further substantiate a central role for mitochondria in the biogenesis of cytosolic Fe-S proteins.
Hum Mol Genet 2006 Mar 15
PMID:The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis. 1646 50

We report the case of a man with severe X-linked sideroblastic anemia, severe iron overload, and hepatic cirrhosis who died of hepatocellular carcinoma. Evaluation of family members using DNA sequencing revealed that he was hemizygous for the novel ALAS2 mutation R452H (exon 9; nt 1407 G --> A). The proband's brother, an ALAS2 R452H hemizygote, had mild anemia and mild iron overload. Four female relatives were ALAS2 R452H heterozygotes, but they had mild or no anemia and no iron overload. Sequencing of TFR2, HFE, FPN1 (SLC40A1), HAMP, HJV, and the erythrocyte pyruvate kinase genes of family members was also performed. We thus detected the novel TFR2 missense mutation I449V (exon 10; nt 1345 A --> G) in the proband's wife and daughter, neither of whom had anemia or iron overload. Possible explanations for the disparate red blood cell and iron phenotypes of the proband and his family members are discussed.
Blood Cells Mol Dis
PMID:Disparate phenotypic expression of ALAS2 R452H (nt 1407 G --> A) in two brothers, one with severe sideroblastic anemia and iron overload, hepatic cirrhosis, and hepatocellular carcinoma. 1654 Mar 54

Historically X-linked sideroblastic anemia, with rare exceptions, was thought to be manifested only in males. Since the discovery of the erythroid-specific isoform of 5-aminolevulinate synthase (ALAS2) and the cloning of its gene (ALAS2) 15 years ago, mutation analysis has revealed that clinical expression of this X-linked disorder is prevalent in females as well. However, presence of the disease in both genders within affected kindreds appears to be very uncommon. We report a unique family with the disorder in three women who have had widely disparate clinical courses. The anemia is associated with a previously unrecognized ALAS2 mutation (Arg436Trp) and is unresponsive to pyridoxine. To clarify the varied clinical courses of the patients, X-chromosome inactivation patterns were examined in hematopoietic and non-hematopoietic cells. We observed inactivation patterns supporting the conclusions that one daughter has a mild phenotype at age 31 because of moderate constitutive skewed X-chromosome inactivation, another daughter with clinical onset at age 16 is severely affected due to extreme constitutive X-skewing, whereas the mother developed progressive anemia in the fifth decade as she acquired an age-related non-random X-inactivation in hematopoietic cells. In addition, we observed random X-inactivation in reticulocytes of all three women that contrasted with a markedly skewed inactivation pattern in bone marrow erythroid cells. This discordance is attributable to apoptosis of erythroid precursors derived from progenitor cells with an active X-chromosome bearing the ALAS2 mutation. The features of the disorder in this family are also instructive in regard to the differential diagnosis of sideroblastic anemias in women.
Blood Cells Mol Dis
PMID:X-linked sideroblastic anemia associated with a novel ALAS2 mutation and unfortunate skewed X-chromosome inactivation patterns. 1673 31

5-Aminolevulinate synthase is a homodimeric pyridoxal 5'-phosphate-dependent enzyme that catalyzes the first step of the heme biosynthetic pathway in animals, fungi, and the alpha-subclass of the photosynthetic purple bacteria. The reaction cycle involves condensation of glycine with succinyl-coenzyme A to yield 5-aminolevulinate, carbon dioxide, and CoA. Mutations in the human erythroid-specific aminolevulinate synthase gene are associated with the erythropoietic disorder X-linked sideroblastic anemia. Recent kinetic and crystallographic data have facilitated an unprecedented understanding of how this important enzyme produces 5-aminolevulinate, and suggest possible directions for future research that may lead to treatments not only for X-linked sideroblastic anemia, but also other diseases.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:5-aminolevulinate synthase: catalysis of the first step of heme biosynthesis. 1926 8


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