A mutation in a mitochondrial transmembrane protein is responsible for the pleiotropic hematological and skeletal phenotype of flexed-tail (f/f) mice

Abstract

We have studied the flexed-tail (f) mouse to gain insight into mammalian mitochondrial iron metabolism. Flexed-tail animals have axial skeletal abnormalities and a transient embryonic and neonatal anemia characterized by pathologic intramitochondrial iron deposits in erythrocytes. Mitochondrial iron accumulation is the hallmark of sideroblastic anemias, which typically result from defects in heme biosynthesis or other pathways that lead to abnormal erythroid mitochondrial iron utilization. To clone the f gene, we used positional cloning techniques, and identified a frameshift mutation in a mitochondrial transmembrane protein. The mutated gene, Sfxn1, is the prototype of a novel family of evolutionarily conserved proteins present in eukaryotes.

Mitochondria in hematopoiesis and hematological diseases

“…In mice, sideroblastic anemias have been reproduced also by mutating the mitochondrial membrane protein, flexed tail (Fleming et al, 2001), and by deleting the antioxydant protein superoxide dismutase-2 that protects cells against mitochondrial superoxide (Friedman et al, 2004). In yeast, mitochondrial Fe accumulation with altered mitochondrial functions can be reproduced by mutating any of the enzymes of the (Fe-S) cluster assembly pathway (Lill and Kispal, 2000).…”

Molecular identification of ancient and modern mammalian magnesium transporters

“…Of the other candidates selected, one was an unnamed predicted protein, the transcript of which was upregulated but did not demonstrate Mg 2ϩ transport when expressed in Xenopus laevis oocytes. The second candidate encoded sideroflexin 4, a known mitochondrial Fe 2ϩ transporter (34). Mutant mitochondrial sideroflexin and aberrant Fe 2ϩ transport have been associated with some anemias (34 ; however, on inspection of the predicted secondary structure, it appeared to encode a soluble protein with no predicted TMs.…”

“…The second candidate encoded sideroflexin 4, a known mitochondrial Fe 2ϩ transporter (34). Mutant mitochondrial sideroflexin and aberrant Fe 2ϩ transport have been associated with some anemias (34 ; however, on inspection of the predicted secondary structure, it appeared to encode a soluble protein with no predicted TMs. Because it did not conform to a hypothetical membrane transporter, we did not investigate it further.…”

Developmental expression of sideroflexin family genes in Xenopus embryos

“…However, a subsequent study demonstrated that it was the mutation of Madh5 that affected the ability of f/f mice to respond to acute anemia and the attribution of Sfxn1 mutation to the f/f phenotypes was in doubt (Lenox et al, 2005). Unlike other MCs, SFXN lacks the canonical internal tripartite structure (Azzi et al, 1993;Fleming et al, 2001). In a substrate specificity assay, rat BBG-TCC (SFXN5) does show a citrate transport activity in vitro (Miyake et al, 2002b).…”

“…Sideroflexin (Sfxn), initially known as citrate transport protein (CTP) in rat (Azzi et al, 1993), was named for the siderocytic anemia and flexed tail phenotype observed in flexed-tail (f) mutant mice, which was supposed to be caused by a frameshift mutation in a mitochondrial transmembrane protein (Fleming et al, 2001). However, a subsequent study demonstrated that it was the mutation of Madh5 that affected the ability of f/f mice to respond to acute anemia and the attribution of Sfxn1 mutation to the f/f phenotypes was in doubt (Lenox et al, 2005).…”