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Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia

Abstract

The sideroblastic anemias are a heterogeneous group of congenital and acquired hematological disorders whose morphological hallmark is the presence of ringed sideroblasts—bone marrow erythroid precursors containing pathologic iron deposits within mitochondria. Here, by positional cloning, we define a previously unknown form of autosomal recessive nonsyndromic congenital sideroblastic anemia, associated with mutations in the gene encoding the erythroid specific mitochondrial carrier family protein SLC25A38, and demonstrate that SLC25A38 is important for the biosynthesis of heme in eukaryotes.

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Figure 1: SLC25A38 phenotypes in human, fish and yeast.

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Acknowledgements

We gratefully acknowledge the participation of all the families with this genetic disorder. We thank P. Drapeau for advice on zebrafish physiology and experimentation and P. Wise and E. Wasson for expert technical assistance. The following agencies provided funding for this project: Genome Canada (M.E.S.), Genome Atlantic (M.E.S.), Nova Scotia Health Research Foundation (M.E.S.), Nova Scotia Research and Innovation Trust (M.E.S.), IWK Health Centre Foundation (M.E.S.), Dalhousie University (M.E.S.), Capital Health Research Fund (M.E.S.), Fonds de la Recherche en Santé de Québec (L.S.-A.), NIH K01 DK074410 (P.J.S.) and NIH R01 DK080011 (M.D.F.), The US Department of Veterans Affairs (S.S.B.), University of Oklahoma Health Sciences Center Provost's Fund (S.S.B.), and the Oklahoma Center for Advancement of Science and Technology (S.S.B.).

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Contributions

D.L.G. oversaw molecular genetic studies. H.J. performed statistical mapping analyses. D.R.C. performed haplotype studies. S.C.E. performed molecular genetic analyses. M.F. participated in clinical ascertainment of the patients. M.D.K. developed and performed mass spectrometric ALA and glycine analyses. M.L. performed zebrafish knockdown studies. M.M. performed molecular genetic analyses. M.N. performed molecular genetic analyses. A.R. participated in clinical ascertainment of the patients. L.S.-A. oversaw zebrafish studies. P.J.S. analyzed the yeast phenotype. A.O. performed haplotype studies. S.S.B. obtained institutional review board approval and consents, collected clinical data and samples and edited the manuscript. M.D.F. oversaw haplotype determinations and yeast genetic studies and co-wrote the manuscript. M.L. and S.D. participated in clinical studies of the study subjects. C.V.F. ascertained the study subjects and performed clinical studies to determine the phenotype. M.E.S. oversaw molecular genetic studies and co-wrote the manuscript.

Corresponding author

Correspondence to Mark E Samuels.

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Supplementary Figures 1–5, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 1367 kb)

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Guernsey, D., Jiang, H., Campagna, D. et al. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet 41, 651–653 (2009). https://doi.org/10.1038/ng.359

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