Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations

Abstract

Background: Sideroblastic anemias are heterogeneous congenital and acquired bone marrow disorders characterized by pathologic iron deposits in mitochondria of erythroid precursors. Among the congenital sideroblastic anemias (CSAs), the most common form is X-linked sideroblastic anemia, due to mutations in 5-aminolevulinate synthase (ALAS2). A novel autosomal recessive CSA, caused by mutations in the erythroid specific mitochondrial transporter SLC25A38, was recently defined. Other known etiologies include mutations in genes encoding the thiamine transporter SLC19A2, the RNA-modifying enzyme pseudouridine synthase 1 (PUS1), a mitochondrial ATP-binding cassette transporter (ABCB7), glutaredoxin 5 (GLRX5), as well as mitochondrial DNA deletions. Despite these known diverse causes, in a substantial portion of CSA cases a presumed genetic defect remains unknown.

Procedure: In the context of the recent discovery of SLC25A38 as a major novel cause, we systematically analyzed a large cohort of previously unreported CSA patients. Sixty CSA probands (28 females, 32 males) were examined for ALAS2, SLC25A38, PUS1, GLRX5, and ABCB7 mutations. SLC19A2 and mitochondrial DNA were only analyzed if characteristic syndromic features were apparent.

Results: Twelve probands had biallelic mutations in SLC25A38. Seven ALAS2 mutations were detected in eight sporadic CSA cases, two being novel. We also identified a novel homozygous null PUS1 mutation and novel mitochondrial DNA deletions in two patients with Pearson syndrome. No mutations were encountered in GLRX5, ABCB7, or SLC19A2.

Conclusions: The remaining undefined probands (43%) can be grouped according to gender, family, and clinical characteristics, suggesting novel X-linked and autosomal recessive forms of CSA.

Figure 1

Categories of Identified mutations in the cohort of patients with congenital sideroblastic anemia. The relative percentages of the disease causing mutations in the entire cohort of 83 initial probands (23 previously found to be ALAS2 defects) are indicated. The distribution probably reflects a degree of referral bias, and so may not be readily generalized.

Figure 2

Sketch of a mitochondrion depicting the sites of the proteins that are defective in the various congenital sideroblastic anemias. Gly – glycine; ALA – 5-aminolevulinic acid; SLC25A38 – mitochondrial carrier protein SLC25A38; ALAS2 – 5-aminolevulinate synthase 2; PLP – pyridoxal 5′-phosphate; SLC19A2 – high-affinity thiamine transporter SLC19A2; mtDNA – mitochondrial DNA; tRNA – transfer RNA; PUS1 – pseudouridine synthase 1; Fe-S – iron-sulfur; GLRX5 – glutaredoxin 5; ABCB7 – ATP-binding cassette transporter ABCB7; MFRN 1 – mitoferrin 1.