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National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

2015 Annual Report of the Division of Intramural Research

Molecular Medicine Program

Director: Tracey A. Rouault, MD

The Molecular Medicine Program (MMP) strives to identify causes and pathophysiology of rare human diseases and evaluate novel treatment approaches though preclinical testing of new therapies and by performing clinical trials. Metabolic disorders that affect hematopoiesis and cause neurodegeneration are common themes. The MMP seeks to apply cutting-edge basic science methods to understand normal and abnormal metabolism and improve health by identifying promising potential solutions, including gene therapy, which can be developed and tested in humans.

Mukherjee lab members

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Members of the Section on Human Iron Metabolism

The Section on Translational Neuroscience, headed by Stephen Kaler, investigates the genetic causes of inherited copper transport diseases and how the responsible genes participate in neurologic processes. The laboratory seeks to dissect and understand disease mechanisms and to use the knowledge gained to improve health through rational treatments, including gene therapy. Kaler identified the molecular basis for occipital horn syndrome and, with international collaborators, delineated the causes of several other conditions affecting copper homeostasis, including ATP7A (a copper pump)–related isolated distal motor neuron degeneration, and unique syndromes caused by mutations in SLC33A1 (an acetylCoA transporter), CCS (a copper chaperone), and AP1S1 (adapter protein complex 1 sigma subunit). The Section pioneered early identification of infants at risk for Menkes disease, using neurochemical plasma measurements, and developed a predictive test for responsiveness to copper treatment of this illness based on residual copper transport activity by certain mutant ATP7A alleles in a yeast complementation assay. The Section recently rescued a lethal mouse model of Menkes disease by brain-directed adeno-associated virus (AAV)–mediated gene addition. Extension of the latter proof-of-concept investigations, in tandem with preclinical toxicology studies, will pave the way for a first-in-human gene therapy trial for Menkes disease patients with complete loss-of-function ATP7A–gene defects. The Section is also working to distinguish the mechanisms responsible for normal copper transport activity from those of intracellular trafficking of ATP7A and of ATP7B, a closely related copper-transporting ATPase.

The Section on Human Iron Metabolism, headed by Tracey Rouault, studies mammalian iron metabolism using mouse models and tissue culture. Rouault previously identified and characterized two major cytosolic iron-regulatory proteins (IRPs 1 and 2). Targeted deletion of IRP2 in mice revealed that misregulation of iron metabolism resulting from loss of IRP2 causes functional iron deficiency, erythropoietic protoporphyria, anemia, and neurodegeneration, which adversely affect motor neurons in particular. The Section has also focused for many years on mammalian iron-sulfur cluster assembly, initially because of its relevance to IRP1 regulation. IRP1–deficient mice develop polycythemia and pulmonary hypertension because of translational derepression of HIF2 alpha (alpha subunit of the hypoxia-inducible factor HIF2). Researchers in the Section characterized numerous mammalian genes involved in iron-sulfur cluster synthesis and developed in vitro and in vivo methods to assess iron-sulfur cluster biogenesis. The Section's discoveries may promote understanding and treatment of neurodegenerative diseases, including Friedreich's ataxia, and hematologic disorders such as refractory anemias and erythropoietic protoporphyria. The Section discovered that the use of Tempol, a stable nitroxide, prevents neurodegeneration in a mouse deficient in IRP2. Using newly developed antisense technology and genetic engineering of stem cells derived from patients with genetic diseases, the Section is pursuing studies to elucidate the pathophysiology and develop treatments for three diseases caused by defects in iron-sulfur cluster biogenesis, including Friedreich's ataxia, ICSU (iron-sulfur cluster assembly enzyme) deficiency myopathy, and GLRX5 (glutaredoxin 5) sideroblastic anemia, as well as mutations in the NFU (iron-sulfur cluster scaffold) gene. The Section is also studying cancers caused by mutations in succinate dehydrogenase subunit B and fumarate hydratase, with emphasis on understanding metabolic remodeling, including changes in iron metabolism that accompany the switch to aerobic glycolysis in cancer. In the past several years, investigators in the Section discovered an important mechanism by which iron-sulfur clusters are delivered to specific recipient proteins. Using the succinate dehydrogenase B subunit (SDHB), they discovered that the HSC20 co-chaperone directly binds to SDHB to include it an iron-sulfur cluster transfer complex. They identified a small peptide motif, LYR, which binds to the C-terminus of SDHB at several points. The LYR motif also is likely to be critical in aiding respiratory chain assembly factors to facilitate correct ligation of iron-sulfur clusters in complexes I–III. Investigators envision that discovery of this motif will lead to discovery of many more mammalian iron sulfur proteins than are now recognized, perhaps changing our understanding of numerous metabolic pathways and the redox state of normal cells.

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