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Autosomal recessive sideroblastic anemia is a severe, transfusion-dependent disorder characterized by ring sideroblasts and microcytic, hypochromic anemia. The mitochondrial carrier SLC25A38 mediates erythroid glycine import for heme synthesis and is uniquely expressed in red cell precursors. Biallelic loss-of-function in SLC25A38 defines a distinct form of congenital sideroblastic anemia (SLC25A38; autosomal recessive sideroblastic anemia).
Genetic studies across diverse populations have identified at least 37 probands with SLC25A38-related disease. In a cohort of 60 congenital sideroblastic anemia patients, 12 harbored biallelic SLC25A38 mutations including frameshift and splice-site alleles (PMID:19731322). Eleven additional patients from European centers exhibited ten distinct variants, comprising premature terminations such as p.Arg117Ter (PMID:21393332). Four unrelated Iranian families (one proband each) showed novel frameshift and missense alleles confirmed by segregation (PMID:29499877). A Cree founder missense variant c.560G>A (p.Arg187Gln) was homozygous in seven individuals, with clinical rescue achieved by early hematopoietic stem cell transplantation (PMID:32790119). Three further cases arose in endemic anemia screening programs (PMID:38360212).
The variant spectrum includes missense substitutions (e.g., p.Arg278Gly, p.Gly228Val), frameshift insertions/deletions (e.g., p.Ala287fs), and splice-site disruptions (e.g., c.793-1G>C). The recurrent founder allele c.560G>A (p.Arg187Gln) underscores population-specific risk and supports consanguineous screening strategies. All reported variants abolish SLC25A38 transport function, consistent with a loss-of-function mechanism.
Functional assays in a zebrafish slc25a38 knockdown model replicate microcytic anemia that is rescued by combined glycine and folate supplementation, confirming the role of impaired glycine import in heme synthesis (PMID:27038157). Although human trials of supplementation showed no significant clinical benefit, these experiments validate the mechanistic link and support haploinsufficiency as the pathogenic basis.
Clinically, SLC25A38 deficiency presents in infancy with severe microcytic, hypochromic anemia, ring sideroblast formation, and early transfusion dependence. Standard management includes regular red blood cell transfusion and iron chelation; pyridoxine therapy is generally ineffective. Curative allogeneic hematopoietic stem cell transplantation before iron overload yields long-term transfusion independence (PMID:32790119).
The substantial genetic evidence from ≥37 probands across >15 unrelated families, recessive segregation, and concordant functional data support a Definitive gene–disease association. Early genetic testing for SLC25A38 informs diagnosis, enables carrier screening in at-risk populations, and guides timely transplant referral. Key take-home: biallelic SLC25A38 variant detection permits precise diagnosis and curative management in autosomal recessive sideroblastic anemia.
Gene–Disease AssociationDefinitiveMultiple cohorts totaling ≥37 probands across >15 unrelated families with recessive segregation and functional concordance Genetic EvidenceStrong37 probands with biallelic SLC25A38 variants, segregation confirmed in multiple pedigrees, variant spectrum includes missense, frameshift, and splice mutations Functional EvidenceModerateZebrafish knockdown model recapitulates anemia and is rescued by glycine/folate supplementation, confirming mechanism of impaired heme synthesis |