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 mutationswere 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.

Unusual clinical expression and long survival of a pseudouridylate synthase (PUS1) mutation into adulthood

“…13 Until now, all patients with PUS1 mutations have MLASA. 4,12,14,15 Our rather unusual observation emphasizes the clinical variability of the disease and the occasionally long survival of congenital mitochondrial translation deficiency. The variable expressivity and relatively favorable outcome of this case of PUS1 mutation, compared with the severity of most reported cases, remains unexplained.…”

“…Systematic analysis of PUS1 in a large series of 60 patients with sideroblastic anemia allowed to exclude this gene in all patients but two who had MLASA. 12 Moreover, PUS1 mutations have also been excluded as a cause of acquired sideroblastic anemia in a series of 37 patients. 13 Until now, all patients with PUS1 mutations have MLASA.…”

Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia

“…In these patients no disease-causative mutation was identified in the coding regions or reported regulatory regions in ALAS2, SLC25A38, GLRX5, ABCB7, PUS1 and SLC19A2, which have been reported to be genes causing CSA 11 (see the Online Supplementary Methods for full details of the methods).…”

Ring sideroblasts and sideroblastic anemias

“…haematologica | 2011; 96(5) Following the identification of mutant SLC25A38 as a novel cause of inherited sideroblastic anemia, Bergmann et al 12 systematically analyzed a cohort of 60 previously unreported patients with congenital sideroblastic anemia, looking for ALAS2, SLC25A38, PUS1, GLRX5, and ABCB7 mutations. Twelve probands had biallelic mutations in SLC25A38, while 7 had ALAS2 mutations and one had a novel homozygous null PUS1 mutation.…”