Sideroblastic Anaemia

Hamel, B.C.J.; Schretlen, E. D. A. M.

doi:10.1007/bf00441138

Cited by 9 publications

(1 citation statement)

References 22 publications

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“…The sideroblastic anemias are a clinically heterogeneous group of disorders resulting from inherited or acquired causes (1,2). The inherited types are X chromosome-linked or autosomal, and the acquired forms are secondary to chemical induction or to inflammatory disease or are idiopathic.…”

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confidence: 99%

Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.

Cotter

Baumann

Bishop

1992

Proc. Natl. Acad. Sci. U.S.A.

141

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Recently, the human gene encoding erythroid-specific -aminolevulinate synthase was localized to the chromosomal region Xp2l-Xq2l, identifying this gene as the logical candidate for the enzymatic defect causing "X -linked" sideroblastic anemia. To investigate this hypothesis, the 11 exonic coding regions of the -aminolevulinate synthase gene were amplified and sequenced from a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia. A single T --A transition was found in codon 471 in a highly conserved region of exon 9, resulting in an ile -+ Asn substitution. This mutation interrupted contiguous hydrophobic residues and was predicted to transform a region of (3-sheet structure to a random-coil structure. Prokaryotic expression of the normal and mutant cDNAs revealed that the mutant construct expressed low levels of enzymatic activity that required higher concentrations of pyridoxal 5'-phosphate to achieve maximal activation than did the normal enzyme. The amino acid substitution occurred in the exon containing the putative pyridoxal 5'-phosphate binding site and may account for the reduced ability of the cofactor to catalyze the formation of 6aminolevulinic acid.The sideroblastic anemias are a clinically heterogeneous group of disorders resulting from inherited or acquired causes (1, 2). The inherited types are X chromosome-linked or autosomal, and the acquired forms are secondary to chemical induction or to inflammatory disease or are idiopathic. Patients in these classifications can be further subdivided into those who are responsive to pyridoxine and those who are refractory. Sideroblastic anemia is classified as a disorder of heme synthesis since the activities of certain heme biosynthetic enzymes were reported to be deficient (3), whereas globin synthesis was normal. Since many patients had reduced 8-aminolevulinate synthase [ALAS; succinylCoA:glycine C-succinyltransferase (decarboxylating); EC 2.3.1.37] enzymatic activity in bone marrow (4, 5) and because pyridoxal 5'-phosphate (PLP), the pyridoxine metabolite, is a required cofactor, ALAS has been suggested as a candidate gene for mutations leading to some types of sideroblastic anemia (6).The human genes encoding the housekeeping and erythroid forms of ALAS were isolated and characterized (7-9). Although the two genes predicted proteins with 59% amino acid identity, they were mapped to different chromosomes by somatic cell hybrid and in situ hybridization methods. The housekeeping gene mapped to chromosome 3p2l, and the erythroid gene was localized to the X chromosomal region Xp2l-Xq2l (9-13). The X-chromosomal assignment suggested that the erythroid form of ALAS (designated ALAS2) might be the enzymatic defect in "X-linked" sideroblastic anemia (XLSA).To investigate this hypothesis, the erythroid ALAS2 coding regions were amplified and sequenced from a male affected with pyridoxine-responsive XLSA. In this communication, an exonic point mutation in the ALAS2 gene that predicted the substitution of asparagine f...

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mentioning

confidence: 99%

Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.

Cotter

Baumann

Bishop

1992

Proc. Natl. Acad. Sci. U.S.A.

141

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Erythropoese

Remmele¹

1984

Pathologie

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A paediatric case of sideroblastic anaemia

Claustres

Bellet

et al. 1986

Eur J Pediatr

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We examined the morphological and functional characteristics of erythroblasts derived from marrow erythroid progenitor cells grown in a methylcellulose microculture, which were taken from a female child with rare atypical sideroblastic anaemia (SA) partially responsive to pyridoxine. Colony formation was within the normal range in three successive cultures (median values: 82.25 CFU-E and 16.4 BFU-E derived colonies/6.6 X 10(4) cells) compared to growth by normal cells (65-315 CFU-E and 9-40 BFU-E). We evaluated in vitro differentiation by biochemical microassay of a cytosol enzyme involved in the haem pathway: uroporphyrinogen I synthase (UROS). The UROS values in the erythroid colonies from SA marrow were at the lowere end of the normal range (median values: 6.7 +/- 0.3 and 14.4 +/- 3.8 pmol uroporphyrinogen/h in CFU-E and BFU-E-derived colonies respectively versus 17.4 +/- 7.3 and 25 +/- 7.2 pmol/h in CFU-E and BFU-E colonies from normal subjects. Ultrastructural examination of the SA erythroblasts from non-cultured bone marrow or derived from cultured BFU-E revealed the characteristic deposition of iron in mitochondria around the nucleus of most cells (ringed sideroblasts). However, the majority of cultured cells had marked dyserythropoietic features, with a large number of bilobulated or trilobulated erythroblasts, multiple cytoplasmic vacuoles, numerous abnormalities of the nucleus, and excessive membrane material beneath the plasma membrane, all features difficult to observe in non-cultured marrows.

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Sideroblastic Anaemia

Cited by 9 publications

References 22 publications

Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.

Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.

Erythropoese

A paediatric case of sideroblastic anaemia

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