PUBLICATION

Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia

Authors

Fernández-Murray, J.P., Prykhozhij, S.V., Dufay, J.N., Steele, S.L., Gaston, D., Nasrallah, G.K., Coombs, A.J., Liwski, R.S., Fernandez, C.V., Berman, J.N., McMaster, C.R.

ID

ZDB-PUB-160129-1

Date

2016

Source

PLoS Genetics 12: e1005783 (Journal)

Registered Authors

Berman, Jason, Coombs, Andrew, Nasrallah, Gheyath, Prykhozhij, Sergey

Keywords

Glycine, Heme, Mitochondria, Serine, Zebrafish, Embryos, Hemoglobin, Anemia

MeSH Terms

Folic Acid/administration & dosage
Folic Acid/metabolism*
Saccharomyces cerevisiae
Mitochondria/metabolism
Mitochondria/pathology
Humans
Animals
Heme/biosynthesis
Mitochondrial Membrane Transport Proteins/genetics*
Mitochondrial Membrane Transport Proteins/metabolism
Anemia, Sideroblastic/genetics*
Anemia, Sideroblastic/metabolism
Anemia, Sideroblastic/pathology
Genetic Diseases, X-Linked/genetics*
Genetic Diseases, X-Linked/metabolism
Genetic Diseases, X-Linked/pathology
Zebrafish
Glycine/administration & dosage
Glycine/metabolism*
Hemoglobins/drug effects
Hemoglobins/metabolism*
Mutation

(all 22)

PubMed

26821380 Full text @ PLoS Genet.

Abstract

Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
slc25a38a	la781Tg	standard conditions	Prim-5	nucleate erythrocyte	RTPCR	Fig. S3
slc25a38a	WT	standard conditions	Prim-15	blood	ISH	Fig. 6
slc25a38a	WT	standard conditions	Prim-5	blood	ISH	Fig. 6
slc25a38a	WT	standard conditions	Prim-5	blood island	ISH	Fig. 6
slc25a38a	WT	standard conditions	Prim-5	brain	ISH	Fig. 6
slc25a38a	WT	standard conditions	Prim-5	optic cup	ISH	Fig. 6
slc25a38a	WT	standard conditions	Prim-5	posterior cardinal vein	ISH	Fig. 6
slc25a38a	WT	standard conditions	Prim-5	somite	ISH	Fig. 6
slc25a38b	la781Tg	standard conditions	Prim-5	nucleate erythrocyte	RTPCR	Fig. S3
slc25a38b	WT	standard conditions	Prim-15	blood	ISH	Fig. 6

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
la781Tg + MO1-slc25a38a + MO1-slc25a38b	standard conditions	Long-pec	nucleate erythrocyte increased size, abnormal	Fig. S4
la781Tg + MO1-slc25a38a + MO1-slc25a38b	standard conditions	Long-pec	nucleate erythrocyte nucleus decondensed, abnormal	Fig. S4
mitfa^w2/w2; mpv17^a9/a9 + MO1-slc25a38a + MO1-slc25a38b	standard conditions	Long-pec	erythroblast increased amount, abnormal	Fig. 6
mitfa^w2/w2; mpv17^a9/a9 + MO1-slc25a38a + MO1-slc25a38b	standard conditions	Long-pec	nucleate erythrocyte hemoglobin complex decreased amount, abnormal	Fig. 6
mitfa^w2/w2; mpv17^a9/a9 + MO1-slc25a38a + MO1-slc25a38b	chemical treatment: glycine, chemical treatment: folic acid	Long-pec	nucleate erythrocyte hemoglobin complex normal amount, ameliorated	Fig. 6
mitfa^w2/w2; mpv17^a9/a9 + MO2-alas2	standard conditions	Long-pec	nucleate erythrocyte hemoglobin complex decreased amount, abnormal	Fig. S5
mitfa^w2/w2; mpv17^a9/a9 + MO2-alas2	chemical treatment: 5-ammoniolevulinate	Long-pec	nucleate erythrocyte hemoglobin complex decreased amount, abnormal	Fig. S5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
a9		Complex	mpv17
la781Tg	Tg(gata1a:GFP)	Transgenic Insertion
w2		Point Mutation	mitfa

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
sideroblastic anemia	mitfa^w2/w2; mpv17^a9/a9 + MO1-slc25a38a + MO1-slc25a38b	standard conditions	TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
alas2	MO2-alas2	MRPHLNO
slc25a38a	MO1-slc25a38a	MRPHLNO
slc25a38b	MO1-slc25a38b	MRPHLNO

Fish

Fish
la781Tg
la781Tg + MO1-slc25a38a + MO1-slc25a38b
mitfa^w2/w2; mpv17^a9/a9 + MO1-slc25a38a + MO1-slc25a38b
mitfa^w2/w2; mpv17^a9/a9 + MO2-alas2
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Fernández-Murray et al., 2016 ZDB-PUB-160129-1 PMID:26821380

Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia

Fernández-Murray et al., 2016

ZDB-PUB-160129-1
PMID:26821380