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Brett Graham

Brett H. Graham

E-mail: bgraham@bcm.edu

Assistant Professor, Baylor College of Medicine

B.A., The University of Tennessee, 1991
M.D., Ph.D., Emory University, Atlanta, GA, 1998
Fellow, Baylor College of Medicine, Houston, TX, 2001-03

Genetics of inborn errors of metabolism; genetic models of mitochondrial disease in Drosophila and mice

Our laboratory is interested in studying the genetics of metabolic function and disease through the manipulation of genetic model systems, particularly the mouse and the fruit fly, Drosophila melanogaster. Specifically, we are interested in the function of the mitochondrion in normal cellular biology and disease. By taking advantage of the strengths of each model system, we intend to dissect the pathophysiology of mitochondrial dysfunction to progress towards the ultimate goal of developing novel therapeutic strategies for diseases that exhibit mitochondrial dysfunction.

We are utilizing mouse embryonic stem (ES) cells in a cell-based forward genetic screen for mutant mitochondrial phenotypes. Fluorescent markers for mitochondrial mass and mitochondrial membrane potential are used in conjunction with fluorescent-activated cell sorting (FACS) for high-throughput phenotyping of ES cells mutagenized by gene trapping or by transfecting pooled shRNAmir libraries. We have also obtained mutant ES clones in genes of interest from the International Gene Trap Consortium. Mutant clones of interest can be characterized on a molecular and cellular level, as well as potentially used to generate transgenic animals. Our goals are to identify novel candidates for mitochondrial disease genes and to develop new animal models of mitochondrial disease for studying pathophysiology and potential therapeutic approaches. From our initial screen, we identified a mutant gene trap ES cell clone for Sucla2, which encodes the ADP-specific β subunit of succinyl-CoA synthetase, a component of the TCA cycle. In humans, SUCLA2 mutations have been demonstrated to cause mitochondrial encephalomyopathy with mitochondrial DNA (mtDNA) depletion. We have used the Sucla2 mutant ES clone to generate a transgenic line and mutant animals exhibit mtDNA depletion and mitochondrial dysfunction in brain and muscle. Characterization of this mutant mouse line will provide insights into the pathophysiology of mtDNA depletion as well as into the fundamental biology of mtDNA maintenance. We are also developing and studying gene trap mutants for components of respiratory chain complexes I, II, and V.

Voltage-Dependent Anion Channels (VDACs or mitochondrial porins) are a family of proteins present in the mitochondrial outer membrane that play a critical role in the regulation of outer membrane permeability. porin is the predominant VDAC in Drosophila. We have generated and been studying hypomorphic mutants of porin. These mutants exhibit defects in energy metabolism, male fertility, and neuromuscular and synaptic function. We recently have performed genetic screens for suppressors of mutant porin phenotypes and are actively working to identify candidate suppressor loci.

Another project in the lab concerns the development of Drosophila models of mitochondrial disease. We have generated and are characterizing null alleles for genes encoding subunits of various complexes of the mitochondrial electron transport chain. The long-term goal of this project is to use these mutant alleles in both genetic and drug modifier screens to identify suppressors of mutant phenotypes that will provide insight into the pathophysiology of mitochondrial disease and potentially provide novel therapeutic strategies and targets.

We are also part of a collaboration designed to identify and validate new mitochondrial disease genes by performing whole exome sequencing of patients with clinically diagnosed mitochondrial disease who do not have an identified underlying molecular etiology. In this project, our lab will be responsible for validating candidate genes in cell culture systems by demonstrating cDNA rescue in patient fibroblasts and/or by mimicking respiratory chain deficiency/mitochondrial respiration defect through knockdown of the candidate gene in wild type cells.

Selected Publications

Brunetti-Pierri N, Mian A, Luetchke R, Graham BH (2007) IUGR and placental vacuolization as presenting features in a case of GM1 Gangliosidosis. Journal of Inherited Metabolic Disease 30:823.

Sano M, Izumi Y, Helenius K, Asakura M, Rossi D, Taffet G, Hu L, Pautler R, Wilson C, Boudina S, Abel ED, Taegtmeyer H, Scaglia F, Graham BH, Kralli A, Shimizu N, Tanaka H, Mäkelä T, Schneider MD (2007) Mènage-á-trois 1 is critical for the transcriptional function of PPAR? coactivator-1. Cell Metabolism 5:129-142.

Brautbar A, Wang J, Abdenur JE, Chang RC, Thomas JA, Grebe TA, Lim C, Weng SW, Graham BH, Wong LJ (2008) The mitochondrial 13513G>A mutation is associated with Leigh disease phenotypes independent of complex I deficiency in muscle. Molecular Genetics and Metabolism 94:485-490.

Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham BH, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, Patel A (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nature Genetics 40:1466-14671.

Craigen WJ, Graham BH (2008) Genetic strategies for dissecting mammalian and Drosophila voltage-dependent anion channel functions. Journal of Bioenergetics and Biomembranes 40:207-212.

El-Hattab AW, Li FY, Shen J, Powell BR, Bawle EV, Adams DJ, Wahl E, Kobori JA, Graham BH, Scaglia F, Wong LJ (2010) Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. Genetics in Medicine 12:19-24.

Franco LM, de Ravel T, Graham BH, Frenkel SM, Van Driessche J, Stankiewicz P, Lupski JR, Vermeesch JR, Cheung SW (2010) A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion. European Journal of Human Genetics 18:258-261.

Graham BH, Li Z, Alesii EP, Versteken P, Lee C, Wang J, Craigen WJ (2010) Neurologic dysfunction and male infertility in Drosophila porin mutants: a new model for mitochondrial dysfunction and disease. Journal of Biological Chemistry 285:11143-11153.

Graham BH (2012) Diagnostic challenges of mitochondrial disorders: complexities of two genomes. Methods in Molecular Biology 837:35-46.

Li Z, Graham BH (2012) Measurement of mitochondrial oxygen consumption using a Clark electrode. Methods in Molecular Biology 837:63-72.

Contact Information

Brett Graham, M.D., Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza T803
Houston, Texas 77030, U.S.A.

Tel: (713) 798-6209
Fax: (713) 798-1445
E-mail: bgraham@bcm.edu

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