ABSTRACT
Sideroblastic anemias (SA) are characterized by iron accumulation in the mitochondria of erythroblasts. Although we have evidence of mitochondrial gene alterations in sporadic congenital cases, the origin of acquired forms [refractory anemia with ring sideroblasts (RARS)], is still largely unknown. Here, we report the analysis of respiratory chain function in a patient with a large mitochondrial deletion and in patients with RARS. A young boy with SA showed symptoms typical of a mitochondrial disease with metabolic acidosis, muscle weakness and cerebral involvement. His bone marrow DNA was analyzed for the presence of mitochondrial deletions. We found a new mitochondrial (mt)DNA deletion spanning 3,614 bp and including all the mt genes encoding complex IV, plus ATPase 6 and 8, and several transfer (t)RNAs. All tissues analyzed (liver, skeletal muscle, brain, pancreas) showed a heteroplasmic distribution of this mutant DNA. Bone marrow homogenates were obtained from five patients with RARS and from three patients with normal bone marrow and respiratory chain function assayed by spectrophotometric analysis. Cytochrome c oxidase (CCO) activity was greatly reduced in the patient's bone marrow. In contrast, CCO activity and global respiratory chain function were conserved in patients with RARS. We conclude that deficient CCO activity secondary to mtDNA deletions is related to intramitochondrial iron accumulation, as in our patient or in those with Pearson's syndrome, whereas other mechanisms, e.g. nuclear DNA mutations, have to be proposed to be involved in the acquired forms of SA.
Subject(s)
Anemia, Sideroblastic/metabolism , Cytochrome-c Oxidase Deficiency/genetics , DNA, Mitochondrial/genetics , Electron Transport Complex IV/genetics , Gene Deletion , Iron/metabolism , Mitochondria/metabolism , Mitochondrial Myopathies/genetics , Mitochondrial Proton-Translocating ATPases/deficiency , Acidosis/genetics , Adolescent , Anemia, Refractory/genetics , Anemia, Sideroblastic/genetics , Bone Marrow/pathology , DNA Mutational Analysis , Disease Progression , Electron Transport , Electron Transport Complex IV/analysis , Fatal Outcome , Heterozygote , Humans , Male , Mitochondrial Myopathies/blood , Mitochondrial Proton-Translocating ATPases/genetics , Mosaicism , RNA, Transfer/genetics , beta-Thalassemia/geneticsSubject(s)
Globins/genetics , Mutation , Thalassemia/genetics , alpha-Thalassemia/genetics , 3' Untranslated Regions/genetics , 5' Untranslated Regions/genetics , Adult , Alleles , Child , Codon/genetics , Codon, Nonsense , DNA Mutational Analysis , Female , Fetal Hemoglobin/analysis , Gene Duplication , Gene Expression Regulation , Genes, Dominant , Genes, Recessive , Genetic Heterogeneity , Humans , Infant, Newborn , Male , Promoter Regions, Genetic/genetics , Regulatory Sequences, Nucleic Acid/genetics , Sequence DeletionABSTRACT
Juvenile hereditary hemochromatosis is a genetically heterogeneous disorder transmitted as an autosomal recessive trait. It is most often caused by mutations in the HJV gene and rarely in the HAMP gene. Hepcidin is considered to constitute a negative regulator of iron absorption, and its production is increased in inflammatory states and iron overload. We report the detection of a new mutation in the HAMP gene leading to juvenile hemochromatosis in 2 members of a Portuguese family. The mutation lies in the 5'-UTR (untranslated region) of the gene and creates a new initiation codon in the context of a Kozak sequence. We found no trace of hepcidin protein in the patients' urine, suggesting that ribosomes select the mutant initiation codon for translation. The decrease of hepcidin production would thus lead to increased iron absorption, resulting in iron deposition in parenchymal tissues. Phlebotomy therapy of the 2 patients resulted in impressive clinical improvement.