INTRODUCTION
The congenital sideroblastic anemias (CSAs) are a heterogeneous group of
inherited disorders of erythropoiesis characterized by pathologic
deposits of iron in the mitochondria of developing erythroblasts
(Cartwright & Deiss, 1975). The
genetically defined CSAs can be attributed to defects in three
interrelated mitochondrial pathways: heme biosynthesis, iron-sulfur
cluster assembly, and mitochondrial protein synthesis and respiration
(Ducamp & Fleming, 2019). CSAs due to
primary heme biosynthesis defects are the most prevalent. The most
common CSA, X-linked sideroblastic anemia (XLSA), is caused by mutations
in the first and rate-limiting enzyme in erythroid heme synthesis,
5-aminolevulinate synthase 2 (ALAS2), which catalyses the condensation
of glycine with succinyl coenzyme A to form 5-aminolevulinic acid (ALA)
in the mitochondrial matrix. More than 200 families with XLSA have been
described in the literature (Bottomley &
Fleming, 2014). ALAS2 is extraordinarily dependent upon high levels of
glycine to ensure sufficient heme synthesis, as it has a very highKm (9.3 ± 1.2 mM) for this substrate
(Bishop, Tchaikovskii, Nazarenko, &
Desnick, 2013).
An autosomal recessive form due to loss-of-function mutations in
SLC25A38 is the second most common form of CSA
(Guernsey et al., 2009). SLC25A38 is a
member of the Mitochondrial Solute Carrier Family 25 (SLC25) family of
transporters (Kunji, 2004;
Ruprecht & Kunji, 2020), is encoded on
chromosome 3p22, and is highly and selectively expressed in
erythroblasts (Guernsey et al., 2009).
The yeast ortholog of SLC25A38 (yDL119c) is essential for efficient heme
biosynthesis and knockdown of the orthologous proteins in zebrafish
results in anemia; each of these phenotypes can be rescued by the
addition of glycine or ALA
(Fernandez-Murray et al., 2016;
Guernsey et al., 2009). Transport studies
show that yDL119c is a high affinity mitochondrial glycine importer
(Lunetti et al., 2016).
While the severity of the anemia is generally far more profound than
XLSA, consistent with the shared interruption of heme synthesis, the
morphologic features of the blood and bone marrow in the SLC25A38 anemia
are highly reminiscent of XLSA and characterized by a reticulocytopenic,
hypochromic, microcytic anemia with a very wide red blood cell
distribution width (RDW) and ring sideroblasts (RS) predominantly found
in later erythroid precursors. To date, 69 families and a total of 36
different causative SLC25A38 mutations have been described
(W. An et al., 2015;
W. B. An et al., 2019;
Andolfo et al., 2020;
Fouquet et al., 2019;
Guernsey et al., 2009;
Kakourou et al., 2016;
Kannengiesser et al., 2011;
Kim, Shah, Bottomley, & Shah, 2018;
Kucerova et al., 2011;
Le Rouzic et al., 2017;
Liu et al., 2013;
Mehri et al., 2018;
Ravindra et al., 2020;
Shefer Averbuch et al., 2018;
Ulirsch et al., 2019;
Uminski et al., 2020;
Wong et al., 2015). Here we describe the
clinical phenotypes and genotypes of an additional 31 individuals from
24 families, including 11 novel mutations. We also review the spectrum
of mutations and genotypes associated with the disease, including
describing the unique localization of missense (MS) mutations in
transmembrane (TM) domains and account for the reoccurrence of several
alleles in different populations.