Missense variants in ALAS 2 gene in five patients

This is the authors' abstract. We don't add key points for this paper.

Sideroblastic anemias (SAs) are a heterozygous group of disorders characterized by the presence of ring sideroblasts in the bone marrow. Congenital sideroblastic anemias are syndromic and nonsyndromic and caused by pathogenic variants in genes involved in heme synthesis, FeS cluster biogenesis, and mitochondrial protein synthesis. ABCB7, SLC19A2, PUS1, YARS2, TRNT1, mitochondrial DNA, and NDUFB11 genes are responsible so far for syndromic CSA (Xlinked SA with spinocerebellar ataxia, thiamineresponsive megaloblastic anemia, myopathy with lactic acidosis and SA, Bcell immunodeficiency with fevers and developmental delay, Pearson marrowpancreas syndrome). ALAS2, SLC25A38, GLRX5, STEAP3, and HSPA9 genes are responsible so far for nonsyndromic CSA (Xlinked SA or XLSA, autosomal recessive SA).1-3 XLSA, OMIM: 300751, is the most common type of nonsyndromic CSA and caused by variants in the erythroidspecific gene coding 5aminolevulinate synthase (ALAS2) localized on chromosome Xp11.21. ALAS (EC 2.3.1.37) is the first enzyme of heme synthesis and catalyzes the condensation of glycine and succinyl coenzyme A into 5aminolevulinic acid (ALA) in the mitochondria.1-3 XLSA patients present variable degrees of anemia, often mild or asymptomatic, recognized in adulthood or later life. Anemia is typically microcytic and hypochromic with poikilocytosis, red blood cell distribution width is usually increased. Nearly onethird of probands are female where anemia results from an X inactivation skewing and is typically nonmicrocytic.1-3 Anemia in many XLSA patients responds variably to supplementation with pyridoxine (vitamin B6) which is converted into pyridoxal 5phosphate (PLP), the active cofactor essential for ALAS2 activity. Due to elevated intestinal absorption of iron, patients will present parenchymal iron overload.1-3 Here, we report five patients with five different variants in ALAS2 gene. We performed in silico analysis of variants and in vitro study to assess functional consequences of the two novel variants in ALAS2.