Barry Paw, MD, PhD

A research team led by Barry Paw, MD, PhD, with Gordon Hildick-Smith (MD candidate, Class of 2017, Weill Cornell Medical College), BWH Division of Hematology, identified genetic mutations that cause mitochondrial diseases and macrocytic anemia (a condition that leads to reduced red blood cell number with enlarged cell size).

Using exome sequencing, researchers were able to identify genetic mutations in the Sideroflexin 4 gene in two children with mitochondrial disease. Of the two cases, the more severe case also presented with macrocytic anemia. The Sideroflexin 4 protein is an uncharacterized mitochondrial protein that resides in the inner membrane of the mitochondria (“power plants” within a cell responsible for generating a cell’s energy supply).

When researchers knocked down the Sideroflexin 4 gene in zebrafish, they observed similar mitochondrial respiratory defects that were seen in the children, as well as macrocytic anemia with megaloblastic features of the more severe case. Moreover, studies with fibroblasts (cells that make collagen and connective tissues) from the affected individuals showed how the Sideroflexin 4 gene was necessary for mitochondrial respiratory homeostasis (the metabolic functions that occur in the mitochondria to generate energy).

Gordon Hildick-Smith

“The identification of these rare mutations in Sideroflexin 4 and their in vivo functional validation shows the power of coupling targeted exome sequencing with the zebrafish system for rapidly identifying and functionally validating disease-causing mutations,” said Paw.

These studies demonstrate the requirement for, the previously unstudied gene, Sideroflexin 4 in mitochondrial homeostasis as well as erythropoiesis. Furthermore, these studies demonstrate that function of vertebrate Sideroflexin 4 has been conserved throughout evolution.

“Mutations in Sideroflexin 4 as a cause for combined anemia and mitochondrial disorder broadens our fundamental knowledge of red blood cell defects,” added Paw. “Further insights into the biochemical function of Sideroflexin 4 may lead to future therapies for anemias.”

The study was published in the November 2013 issue of The American Journal of Human Genetics.