Assistant Professor, Department of Molecular and Human Genetics

B.A., The University of Tennessee, 1991
M.D., Ph.D., Emory University, 1998
Pediatric Residency, Baylor College of Medicine, 1998-2001
Fellow in Medical Genetics, Baylor College of Medicine, 2001-2003

RESEARCH INTERESTS:
Our laboratory is interested in studying the genetics of metabolic function and disease through the manipulation of genetic model systems, particularly the fruit fly, Drosophila melanogaster, and the mouse. 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 diseases to progress towards the ultimate goal of developing novel therapeutic strategies for this group of diseases.

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 a severely hypomorphic mutant of porin. This mutant exhibits defects in energy metabolism, male fertility, and neuromuscular and synaptic function. These mutant phenotypes are similar to ones observed in mammalian VDAC mutants, demonstrating conservation of function and the relevance of Drosophila as a model for mitochondrial function. Recently we have performed a genetic screen 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 are interested in fly genes that are known or predicted orthologs of human nuclear-encoded mitochondrial disease genes. Starting with P element insertions in genes encoding components of the mitochondrial respiratory chain, we are using P element-mediated imprecise excision to generate series of mutant alleles (hypomorphic to null) for characterization and phenotypic analysis. The long-term goal of this project is to use these mutant alleles in 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.

In addition to fruit fly models of mitochondrial dysfunction and disease, we are also using 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. Mutant clones of interest can be characterized on a molecular and cellular level, as well as potentially used to generate transgenic animals. Our goal is to identify novel candidates for mitochondrial disease genes and to develop new animal models of mitochondrial disease for studying pathophysiology and potential therapeutic approaches.

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SELECTED PUBLICATIONS:
1. Brunetti-Pierri N, Mian A, Luetchke R, Graham BH (2007). IUGR and placental vacuolization as presenting features in a case of GM1 Gangliosidosis. J. Inherit. Metab. Dis., in press.

2. Holder AM, Graham BH, Lee B, Scott DA (2007). Fine-Lubinsky Syndrome: Sibling Pair Suggests Possible Autosomal Recessive Inheritance. Am. J. Med. Genet. A. Mar 29 [Epub ahead of print].

3. 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). Ménage-à-trois 1 is critical for the transcriptional function of PPARγ coactivator-1. Cell Metab. 5: 129-142.

4. Graham BH, Craigen WJ (2005). Mitochondrial voltage-dependent anion channel gene family in Drosophila melanogaster: complex patterns of evolution, genomic organization, and developmental expression. Mol. Genet. Metab. 85: 308-317.

5. Graham BH, Craigen WJ (2004). Genetic approaches to analyzing mitochondrial outer membrane permeability. Curr. Top. Dev. Biol. 59: 87-118.

6. Komarov AG, Graham BH, Craigen WJ, Colombini M (2004). The physiological properties of a novel family of VDAC-like proteins from Drosophila melanogaster. Biophys. J. 86: 152-162.

7. Graham BH, Bacino CA (2003). Male patient with non-mosaic deleted Y-chromosome and clinical features of Turner syndrome. Am. J. Med. Genet. A. 119: 234-237.

8. Graham BH, Sweatt JD, Craigen WJ (2002). Noninvasive, in vivo approaches to evaluating behavior and exercise physiology in mouse models of mitochondrial disease. Methods 26: 364-370.

9. Graham BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR, Wallace DC (1997). A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat. Genet. 16: 226-234.

For more publications, see listing on Pub Med.

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CLINICAL INFORMATION:
Board Certifications:
Pediatrics
Clinical Genetics

Primary Focus:
Genetic Disorders,
Metabolic Disorders

Professional Organizations:
Member, American Society of Human Genetics
Member, Society of Inherited Metabolic Disorders
Member, Society for the Study of Inborn Errors of Metabolism

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cONTACT INFORMATION:
Brett Graham, M.D., Ph.D.
Baylor College of Medicine
Dept of Molecular and Human Genetics
One Baylor Plaza, Rm. T526
Houston, Texas 77030

Telephone: 713-798-6209
Fax: 713-798-4329
E-mail:

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Last modified: 6/2007