Brett Graham, M.D., Ph.D.
Assistant Professor of Molecular and Human Genetics
Assistant Professor, Programs in Developmental Biology and Translational Biology & Molecular Medicine
Assistant Professor, The Houston Laboratory and Population Sciences Training Program in Gene-Environment Interaction
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
American Board of Pediatrics
American Board of Medical Genetics: Clinical Genetics and Medical Biochemical Genetics
Member, American Society of Human Genetics
Member, Society of Inherited Metabolic Disorders
Member, Society for the Study of Inborn Errors of Metabolism
Genetic Disorders and Metabolic Disorders
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.
From a cell-based forward genetic screen for mutant mitochondrial phenotypes, we identified a mutant gene trap mouse embryonic stem (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 embryos exhibit mtDNA depletion and mitochondrial dysfunction in brain and muscle. Characterization of this mutant mouse line and cellular function studies in mutant mouse embryonic fibroblasts (MEFs) will provide insights into the pathophysiology of TCA cycle dysfunction and 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. In particular, we have been studying flies mutant for NDUFS3, a structural subunit of mitochondrial complex I. Mutant animals exhibit complex I deficiency and neurological dysfunction manifested by locomotor defects, increased sensitivity to mechanical stress (“bang sensitivity”), and progressive deterioration of retinal function as measured by electroretinogram (ERG). These animals also exhibit increased oxidative stress and mutant phenotypes are partially ameliorated by supplementation with antioxidants. We are currently performing a pilot drug suppressor screen designed to detect improvements in the ERG. 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 involved in projects 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 participates by validating candidate genes in cell culture systems by demonstrating cDNA rescue of cellular respiration defects in patient fibroblasts and/or by mimicking respiratory chain deficiency/mitochondrial respiration defect through knockdown of the candidate gene in wild type cells.
- 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. J. Biol. Chem. 285(15): 11143-53. PubMed PMID: 20110367
- Wang J, Schmitt ES, Landsverk ML, Zhang VW, Li FY, Graham BH, Craigen WJ, Wong LJ (2012). An integrated approach for classifying mitochondrial DNA variants: one clinical diagnostic laboratory's experience. Genet. Med. 14(6): 620-6. PubMed PMID: 22402757
- Kang P, Lee HK, Glasgow SM, Finley M, Donti T, Gaber ZB, Graham BH, Foster AE, Novitch BG, Gronostajski RM, Deneen B (2012). Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. Neuron 74(1): 79-94. PubMed PMID: 22500632
- Bayat V, Thiffault I, Jaiswal M, Tétreault M, Donti T, Sasarman F, Bernard G, Demers-Lamarche J, Dicaire MJ, Mathieu J, Vanasse M, Bouchard JP, Rioux MF, Lourenco CM, Li Z, Haueter C, Shoubridge EA, Graham BH, Brais B, Bellen HJ (2012). Mutations in the mitochondrial methionyl-tRNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLoS Biol. 10(3): e1001288. PubMed PMID: 22448145
- Bainbridge MN, Hu H, Muzny DM, Musante L, Lupski JR, Graham BH, Chen W, Gripp KW, Jenny K, Wienker TF, Yang Y, Sutton VR, Gibbs RA, Ropers HH (2013). De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome. Genome Med. 5(2): 11. PubMed PMID: 23383720
- Tang S, Wang J, Zhang VW, Li FY, Landsverk M, Cui H, Truong CK, Wang G, Chen LC, Graham B, Scaglia F, Schmitt ES, Craigen WJ, Wong LJ (2013). Transition to next generation analysis of the whole mitochondrial genome: a summary of molecular defects. Hum. Mutat. 34(6): 882-93. PubMed PMID: 23463613
- Cui H, Li F, Chen D, Wang G, Truong CK, Enns GM, Graham B, Milone M, Landsverk ML, Wang J, Zhang W, Wong LJ (2013). Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders. Genet. Med. 15(5): 388-94. PubMed PMID: 23288206
- Zhang K, Li Z, Jaiswal M, Bayat V, Xiong B, Sandoval H, Charng WL, David G, Haueter C, Yamamoto S, Graham BH, Bellen HJ (2013). The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit. J. Cell Biol. 200(6): 807-20. PubMed PMID: 23509070
- Craigen WJ, Graham BH, Wong LJ, Scaglia F, Lewis RA, Bonnen PE (2013). Exome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology. BMC Med. Genet. 14: 83. PubMed PMID: 23947751
- Bonnen PE, Yarham JW, Besse A, Wu P, Faqeih EA, Al-Asmari AM, Saleh MA, Eyaid W, Hadeel A, He L, Smith F, Yau S, Simcox EM, Miwa S, Donti T, Abu-Amero KK, Wong LJ, Craigen WJ, Graham BH, Scott KL, McFarland R, Taylor RW (2013). Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance. Am. J. Hum. Genet. 93(3): 471-81. PubMed PMID: 23993193
Awards and Honors
2006: ASCI Travel Award to attend 2006 ASCI/AAP meeting, Chicago, IL.
2005-2007: Basil O’Connor Scholar Award recipient, March of Dimes
2003-2008: Mentored Clinical Scientist Development Award (K08), NIH/NICHD
2003: Society of Inherited Metabolic Diseases Travel Award to attend 2003 International Congress of Inborn Errors of Metabolism in Brisbane, Australia
2003: Young Investigator Research Grant Award, American Academy of Pediatrics (AAP) Section
2003-2004: Children’s Health Research Center Scholar, Baylor College of Medicine
2003: NRSA Postdoctoral Fellowship
Brett Graham, M.D., Ph.D.
Baylor College of Medicine
Dept of Molecular and Human Genetics
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.