Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 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.
 ...
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

The erythroid-specific (ALAS2) and housekeeping (ALAS1) genes encoding delta-aminolevulinate synthase have recently been mapped to chromosomes Xp21.1----q21 and 3p21, respectively. The erythroid-specific gene is a candidate for mutations resulting in X-linked sideroblastic anemia. Analysis of DNA from hybrid clones containing translocations in the region Xp11.21----Xq21.3 permitted the finer localization of the ALAS2 gene with respect to other loci and breakpoints within this region. These studies localized the ALAS2 gene to the distal subregion of Xp11.21 in Interval 5 indicating the following gene order: Xpter-OATL2-[L62-3A, Xp11.21; A62-1A-4b, Xp11.21]-(ALAS2, DXS323)-[B13-3, Xp11.21; C9-5, Xp11.21]-(DXS14, DXS429)-DXS422-(DXZ1, Xcen). Thus, the reported linkage of acquired sideroblastic anemia and sideroblastic anemia with ataxia to Xq13 presumably results from genes other than ALAS2.
 ...
PMID:Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to a distal subregion of band Xp11.21 by PCR analysis of somatic cell hybrids containing X; autosome translocations. 157 84

Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and ataxia. Two-point analysis with a DNA probe for phosphoglycerate kinase (PGK1), which maps to Xq13, suggested linkage to the disorder by a lod score of at least 2.60 at a recombination fraction of zero. The disease in this kindred appears to be clinically and genetically distinct from that in previously reported families with X-linked hereditary ataxia or spastic paraparesis. No mapping data are available for inherited X-linked sideroblastic anemia without neurologic abnormalities. However, structural alterations of band Xq13 may be involved in the development of idiopathic acquired sideroblastic anemia. No alterations in the restriction patterns of two X-linked genes involved in erythrocyte formation-i.e., a DNA-binding protein (GF-1) and 5-aminolevulinate synthase (ALAS)-were detected in DNA from affected males, arguing against a large deletion in either of these candidate genes.
 ...
PMID:X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. 167 20

The startling morphological abnormalities of sideroblastic anaemia contrasts our uncertainty about its cause. Studies are hampered by the fact that the abnormality resides in the dividing and differentiating erythroblast which is difficult to obtain pure and in large numbers, and in which many levels of metabolic control must coexist. Recent molecular biology approaches have confirmed abnormalities of erythroid delta-aminolaevulinic acid synthase as the cause of X-linked, pyridoxine-responsive sideroblastic anaemia and mitochondrial DNA deletions as the most common cause of congenital macrocytic sideroblastic anaemia. They have also identified a second X-linked sideroblastic anaemia locus linked to phosphoglycerate kinase and associated with ataxia. An association between sideroblastic anaemia and the use of an oral copper chelating agent has highlighted unexplained links between erythroid copper and iron metabolism. Management decisions in relation to pyridoxine treatment, iron reduction, family studies, genetic counselling and antenatal diagnosis have in recent years become of practical relevance to families with known cases of congenital sideroblastic anaemia and careful documentation of the clinical outcome of these cases and of other family members is invaluable. Parallel and integrated studies on the molecular biology of erythroid differentiation are revealing the range of possible controlling influences on erythroblasts and defining the circumstances for each, allowing studies on the cause of the most prevalent form of sideroblastic anaemia (the idiopathic acquired form) and those inherited forms that are not X-linked to be approached with a much clearer perspective.
 ...
PMID:Sideroblastic anaemia. 788 Nov 57

We isolated a novel human ATP-binding cassette (ABC) transporter cDNA, determined its nucleotide sequence, and designated it human ABC7 (hABC7). The nucleotide sequence was highly homologous to the ATM1 gene in yeast, which encodes an ABC transporter (yAtm1p) located in the mitochondrial inner membrane. The deduced human product, a putative half-type transporter, consists of 752 amino acids that are 48.9% identical to those of yAtm1p. A computer-assisted protein structural and localization analysis revealed that the mitochondrial targeting signal of yAtm1p is conserved in the N-terminal region of the primary sequence of the hABC7 protein, and therefore this product is also likely to be located in the mitochondrial inner membrane. The evidence strongly suggests that the hABC7 gene is a counterpart of ATM1 and that its product is probably involved in heme transport. We mapped the hABC7 gene to chromosome Xq13.1-q13.3 by fluorescence in-situ hybridization. As band Xq13 has been implicated in X-linked sideroblastic anemia with spinocerebellar ataxia, hABC7 becomes a candidate gene for this heritable disorder.
 ...
PMID:Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia. 962 16

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.
 ...
PMID:Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). 1019 63

Remarkable progress is being made in understanding the molecular basis of disorders of human iron metabolism. Recent work has uncovered unanticipated relationships with the immune and nervous systems, intricate interconnections with copper metabolism, and striking homologies between yeast and human genes involved in the transport of transition metals. This review examines the clinical consequences of new insights into the pathophysiology of genetic abnormalities affecting iron metabolism. The proteins recently found to be involved in the absorption, transport, utilization, and storage of iron are briefly described, and the clinical manifestations of genetic disorders that affect these proteins are discussed. This chapter considers the most common inherited disorder in individuals of European ancestry (hereditary hemochromatosis), a widespread disease in sub-Saharan populations for which the genetic basis is still uncertain (African dietary iron overload), and several less frequent or rare disorders (juvenile hemochromatosis, atransferrinemia, aceruloplasminemia, hyperferritinemia with autosomal dominant congenital cataract, Friedreich's ataxia, and X-linked sideroblastic anemia with ataxia).
 ...
PMID:Genetic disorders affecting proteins of iron metabolism: clinical implications. 1077 76

A number of ataxias have been shown to result from defects in mitochondrial function. The genes responsible for Friedreich ataxia (FRDA) and for X-linked sideroblastic anemia with ataxia are nuclear genes that encode mitochondrial proteins. These genes, which are highly conserved in species as diverse as humans and yeast, play a role in mitochondrial iron metabolism and in the formation of iron-sulfur clusters. Defects in vitamin E metabolism, due to mutations in tocopherol transfer protein (TTP), also result in ataxia. It is hypothesized that the biochemical feature common to these ataxias is increased oxidant damage either through increased oxidants or decreased anti-oxidants.
 ...
PMID:Spinocerebellar ataxias due to mitochondrial defects. 1185 Jan 12

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.
 ...
PMID:The human ATP-binding cassette transporter genes: from the bench to the bedside. 1189 42

The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders defined by the presence of pathologic iron deposits in erythroblast mitochondria. While the pathogenesis of almost all cases of acquired sideroblastic anemia is unknown, the molecular genetic basis for several of the inherited forms have now been described. Initially, mutations in ALAS2 in X-linked sideroblastic anemia (XLSA) focused attention on the heme biosynthetic pathway as a primary cause of sideroblastic anemia. However, the subsequent description of the genes involved in XLSA with ataxia, thiamine-responsive megaloblastic anemia, and Pearson marrow-pancreas syndrome have implicated other pathways, including mitochondrial oxidative phosphorylation, thiamine metabolism, and iron-sulfur cluster biosynthesis, as primary defects in sideroblastic anemias that may only secondarily impact heme metabolism.
 ...
PMID:The genetics of inherited sideroblastic anemias. 1238 2


1 2 3 Next >>