Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4
Gordon J Hildick-Smith1, Jeffrey D Cooney, Caterina Garone
1Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Abstract:
We used exome sequencing to identify mutations in sideroflexin 4 (SFXN4) in two children with mitochondrial disease (the more severe case also presented with macrocytic anemia). SFXN4 is an uncharacterized mitochondrial protein that localizes to the mitochondrial inner membrane. sfxn4 knockdown in zebrafish recapitulated the mitochondrial respiratory defect observed in both individuals and the macrocytic anemia with megaloblastic features of the more severe case. In vitro and in vivo complementation studies with fibroblasts from the affected individuals and zebrafish demonstrated the requirement of SFXN4 for mitochondrial respiratory homeostasis and erythropoiesis. Our findings establish mutations in SFXN4 as a cause of mitochondriopathy and macrocytic anemia.
Insights
Mutations in sideroflexin 4 (SFXN4) cause mitochondrial disease and macrocytic anemia. SFXN4 is crucial for mitochondrial function and red blood cell production.
Area of Science:
- Genetics
- Molecular Biology
- Hematology
Background:
- Mitochondrial diseases are a group of inherited metabolic disorders.
- Macrocytic anemia, characterized by enlarged red blood cells, can have various causes.
- The role of sideroflexin 4 (SFXN4) in human disease was previously uncharacterized.
Purpose of the Study:
- To identify the genetic cause of mitochondrial disease and macrocytic anemia in two affected children.
- To investigate the function of sideroflexin 4 (SFXN4) in mitochondrial homeostasis and erythropoiesis.
Main Methods:
- Exome sequencing was performed to identify mutations.
- SFXN4 protein localization was determined.
- Zebrafish models were used for knockdown studies and complementation assays.
- Fibroblast cell lines from patients were utilized for in vitro and in vivo studies.
Main Results:
- Exome sequencing identified mutations in SFXN4 in both patients.
- SFXN4 localizes to the mitochondrial inner membrane.
- SFXN4 knockdown in zebrafish replicated the observed mitochondrial respiratory defects and macrocytic anemia.
- Complementation studies confirmed SFXN4's essential role in mitochondrial function and red blood cell development.
Conclusions:
- Mutations in SFXN4 are a newly identified cause of mitochondriopathy and macrocytic anemia.
- SFXN4 is essential for maintaining mitochondrial respiratory homeostasis.
- SFXN4 plays a critical role in erythropoiesis.
More Related Videos
09:40Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle
Published on: January 19, 2017
08:53Author Spotlight: Advancing Erythropoiesis Research - A Simplified Pipeline for Assessing Hematopoietic Stem Cell Function in Myelodysplastic Syndromes
Published on: January 10, 2025
Related Concept Videos
01:31Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
01:31Translation
Translation Produces the Building Blocks of Life
Proteins are...
01:20Inborn Errors of Metabolism
01:27Disorders of Erythrocytes
Erythrocyte disorders can be broadly categorized into two main types: anemic and polycythemic conditions.
A low oxygen-carrying capacity of the blood due to the loss, lower production, or destruction of erythrocytes is termed anemia. Hemorrhagic anemia, for example, occurs when bleeding from an external wound or internal ulcer reduces erythrocyte counts.
On the other...
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:29Cardiomyopathy IV: Restrictive Cardiomyopathy