Anemia, Sideroblastic, 3, Pyridoxine-Refractory

A number sign (#) is used with this entry because of evidence that sideroblastic anemia-3 (SIDBA3), which is refractory to pyridoxine treatment, is caused by homozygous or compound heterozygous mutation in the GLRX5 gene (609588) on chromosome 14q32.

Description

Sideroblastic anemia-3 is an autosomal recessive hematologic disorder characterized by onset of anemia in adulthood. Affected individuals show signs of systemic iron overload, and iron chelation therapy may be of clinical benefit (summary by Liu et al., 2014).

For a discussion of genetic heterogeneity of sideroblastic anemia, see SIDBA1 (300751).

Clinical Features

Camaschella et al. (2007) reported a 60-year-old southern Italian man, born of consanguineous parents, who presented with severe microcytic anemia, jaundice, hepatosplenomegaly, iron overload, cirrhosis, and type II diabetes. Bone marrow showed moderate erythroid expansion and increased iron staining both in erythroblasts and macrophages, with 28% ringed sideroblasts. Folic acid and vitamin B6 supplementation was ineffective. Iron chelation therapy resulted in clinical improvement. Further analysis showed dysregulation of iron-regulatory proteins aconitase (ACO1; 100800) and IREB2 (147582).

Liu et al. (2014) reported a 46-year-old Chinese man who had severe anemia since age 29 years. Features included dark skin, hepatosplenomegaly, anisocytosis on peripheral blood smear, and 19% ringed sideroblasts on bone marrow biopsy. Liver biopsy showed increased iron in parenchymal cells. The anemia was responsive to iron chelation therapy, but not vitamin B6 supplementation. The patient also developed type II diabetes. Peripheral blood cells showed decreased Fe-S-ACO1 protein levels and decreased activity of aconitase compared to controls.

Inheritance

The transmission pattern of SIDBA3 in the family reported by Camaschella et al. (2007) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a southern Italian man with SIDBA3, Camaschella et al. (2007) identified a homozygous mutation in the GLRX5 gene (609588.0001). The was considered to be the human counterpart of the zebrafish shiraz mutant, which shows a similar but more severe phenotype due to a deletion in the Glrx5 gene (see ANIMAL MODEL and Wingert et al., 2005).

In a Chinese man with SIDBA3, Liu et al. (2014) identified compound heterozygous missense mutations in the GLRX5 gene (K101Q, 609588.0002 and L148S, 609588.0003). Direct functional studies of the variants were not performed, but mitochondrial Fe-S biogenesis was impaired in patient peripheral blood cells, as demonstrated by decreased ferrochelatase (FECH; 612386) levels.

Pathogenesis

Ye et al. (2010) found undetectable GLRX5 protein levels in cells derived from the patient reported by Camaschella et al. (2007). Mitochondrial aconitase (ACO2; 100850) activity was undetectable, and cytosolic aconitase (ACO1; 100880) activity was decreased to less than 10% of controls. Mitochondrial complex I activity was also decreased to 20% of normal, consistent with a defect in Fe-S cluster biogenesis. Defects in Fe-S cluster biogenesis negatively impacted ALAS2 (301300) activity and heme biosynthesis. FECH levels were decreased in patient lymphoblast cells, but not in patient fibroblasts, further suggesting that GLRX5 has a specific role in hematopoietic cells. However, patient fibroblasts showed punctate iron deposition in a pattern consistent with mitochondrial iron overload. Transfection of patient cells with wildtype GLRX5 rescued morphologic and growth defects and biochemical abnormalities.

Animal Model

Wingert et al. (2005) showed that the hypochromic anemia in 'shiraz' (sir) zebrafish mutants is caused by deficiency of grx5, a gene required in yeast for Fe/S cluster assembly. Wingert et al. (2005) found that grx5 is expressed in erythroid cells of zebrafish and mice. Zebrafish grx5 rescued the assembly of delta-grx5 yeast Fe/S, showing that the biochemical function of grx5 is evolutionarily conserved. In contrast to yeast, vertebrates use iron regulatory protein-1 (IRP1; 100880) to sense intracellular iron and regulate mRNA stability or the translation of iron metabolism genes. Wingert et al. (2005) found that loss of Fe/S cluster assembly in sir animals activated IRP1 and blocked heme biosynthesis catalyzed by aminolevulinate synthase-2 (ALAS2; 301300). Overexpression of ALAS2 RNA without the 5-prime iron response element that binds IRP1 rescued sir embryos, whereas overexpression of ALAS2, including the iron response element, did not. Further, antisense knockdown of IRP1 restored sir embryo hemoglobin synthesis. Wingert et al. (2005) concluded that their findings uncover a connection between heme biosynthesis and Fe/S clusters, indicating that hemoglobin production in the differentiating red cell is regulated through Fe/S cluster assembly.