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Mark D. Fleming, MD/PhD
Assistant Professor of Pathology
Harvard Medical School
Assistant in Medicine
Brigham and Women's Hospital,
Children's Hospital and Dana Farber Cancer Center

MRRC Project(s)

R01 HL 074247
nm1054: A New Murine Iron Deficiency Anemia Mutant

R01 DK 062474
Sideroflexin 1 and Mitochondrial Iron Metabolism

 
The laboratory has two ongoing projects that involve the development and/or metabolic abnormalities of the central nervous system.

The first project involves the positional cloning of a murine spontaneous mutant nm1054. These animals have hydrocephalus, male infertility, sinusitis, failure to thrive, skin abnormalities, and a moderately severe hypochromic, microcytic anemia. The underlying genetic abnormality is a deletion of approximately 400 kb of DNA that deletes at least 5 genes. Bacterial artificial chromosome (BAC) transgenics demonstrate that a single gene is responsible for the hydrocephalus, male infertility, and sinusitis. Together, this triad of phenotypes resembles Kartegener's syndrome/immotile cilia syndrome/ primary ciliary dyskinesis seen in humans. The other phenotypes are due to deletion of the other genes in the interval. The immotile cilia syndrome gene is a novel protein with weak homology to another protein previously implicated in a congenital hydrocephalus syndrome in mice. Ongoing studies aim to delineate the function of this protein in cilia formation, the pathogenesis of the hydrocephalus, and the relationship to congenital forms of immotile cilia syndrome and congenital hydrocephalus in humans.

The second project involves the in vivo functional characterization of the mitochondrial ATP-binding cassette protein ABCB7, partial loss of function mutations of which are associated with the disorder X-linked sideroblastic anemia with ataxia (XLSA/A). XLSA/A is characterized by a developmental cerebellar hypoplasia and a non- or slowly-progressive cerebellar ataxia. Patients also typically have a mild sideroblastic anemia and may have mild mental retardation. ABCB7 is thought to participate in the "export" of a component required for cytoplasmic iron-sulfur (Fe/S) cluster biogenesis out of mitochondria. Using targeted mutagenesis in murine ES cells, we have created a conditional allele and a point mutated allele in Abcb7. (The initial gene targeting of the conditional allele and the blastocyst injections were performed by the MRRC Gene Manipulation Core Facility). Our current investigations are toward understanding the specific metabolic abnormalities caused by partial loss of function mutations in this gene and how they relate to the CNS and blood phenotypes.