Faculty Biography

Dr. Kit Sing (Paul) Au, Ph.D.

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Education:

Ph.D., Baylor College of Medicine, Houston, Texas

M.Phil, Microbiology, Chinese University of Hong Kong

B.S., Biology, Chinese University of Hong Kong

Clinical and Research Interests:

1. Tuberous sclerosis complex
2. Neural tube defects

Our laboratory researches focus on two human genetic diseases: tuberous sclerosis complex and neural tube defects.

Tuberous sclerosis complex (TSC) is a human dominantly inherited disease. Loss of function of TSC genes predisposes patients to hamartomas and hamartias formation in virtually every organ system. Other disease symptoms include seizure, learning disability and mental retardation. Two genes have been identified to cause the diseases and they are TSC1 on 9q34.3 and TSC2 on 16p13.3. The gene products, tuberin and hamartin, were identified to regulate cell signaling pathways including the mTOR/Akt/PKB, the Wnt/GSK3/ AMPK and cell proliferation regulators: cdk2/cdk4/cdk6 and p27Kip1. TSC2 gene product, tuberin, could potentially participate in these signaling pathways involving growth factors, nutrients, ions, DNA damage and repair. The TSC1 gene product, hamartin, has an ERM domain and a coiled-coil domain important for protein dimerization. Hamartin also interacts with neurofilament light chain and potentially regulate cytoskeleton scaffold formation and intracellular vesicle transportation.

Interestingly, clinical symptoms vary widely among patients with TSC. We used cDNA expression microarray technologies to obtain global gene expression patterns from hamartomas isolated from patients with TSC and identified genes with altered expressions such as PLD1 and HTR2C. We are examining these factors for their involvement in the clinical presentations among TSC patients that may lead to potential treatments strategies.

To help patients to identify their mutations, we have developed a direct sequencing protocol and identified pathogenic mutation for 300 patients. Other mutation identification protocols we explore are: endonuclease based mis-match/repair assays to identify mosaic mutations and mutations in the untranslated regions of TSC1 and TSC2 genes among patients with no mutation identified in the coding exons.

The second major project in the laboratory is applying our experience in mapping TSC genes to map genes involving in neural tube defects (Spina Bifida menningomyeloceles, SBMM, in particular). American of Mexican descents appears to have higher risks of SBMM in the USA.  We are interested in identifying genes that contribute to the higher SB risk in these ethnic groups and the general USA population. A candidate gene association testing approach is adopted using various genetic markers (STR, RFLP, and SNPs). We demonstrated significant risk of SBMM were associated with SNPs in several genes in the folate metabolism pathways (e.g. MTHFR, MTRR, DHFR, CBS, TYMS, and FLOR1) and several genes in the glucose homeostasis regulation pathways (e.g.GLUT1, HK1, LERP, BRCA1 and CBP) among our patients. Our goals are to identify genetic variants within these genes to study the mechanisms that contribute to the risk of SBMM.

Publications (selected):

• Martinez CA, Northrup H, Lin J-I, Morrison AC, Fletcher JM, Tyerman GH, Au KS. Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida. Am J Obstet Gynecol 2009 (submitted)
• Au KS, Ward CH and Northrup H. Tuberous sclerosis complex: disease modifiers and treatments. Curr Opin Pediatr 2008, 20(6):628-633.
• Au KS, Tran PX, Tsai CC, O¢Byrne MR, Lin J-I, Morrison AC, Hampson AW, Cirino P, Fletcher JM, Ostermaier KK, Tyerman GH, Doebel S, Northrup H. Characteristics of a Spina Bifida Population Including North American Caucasian and Hispanic Individuals. Birth Defects Res Part A: Clin Mol Teratol 2008, 82(10):692-700.
• Northrup H, Au KS: Tuberous sclerosis complex, GeneClinics, University of Washington, Pagon RS (ed.). Web site: http://www.geneclinics.org/profiles/tuberoussclerosis/index.html. Updated 2008.
• Davidson CM, Northrup H, King TM, Fletcher JM, Townsend I, Tyerman GH, Au KS. Genes in Glucose Metabolism and Association with Spina Bifida. Reprod Sci. 2008, 15(1):51-8.
• Lim SD, Stallcup W, Lefkove B, Govindarajan B, Au KS, Northrup H, Lang D, Fisher DE, Patel A, Amin MB, Arbiser JL.Expression of the neural stem cell markers NG2 and L1 in human angiomyolipoma: are angiomyolipomas neoplasms of stem cells? Mol Med. 2007, 13(3-4):160-5.
• Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, Delgado MR, Wheless JW, Baumgartner JE, Roa BB, Wilson AM, Smith-Knuppel TK, Cheung MC, Whittermore VH, King TM, Northrup H. Genotype/Phenotype Correlation in 325 Individuals Referred for a Diagnosis of Tuberous Sclerosis Complex in United States. Genetics in Medicine 2007, 9(2):88-100.
• Kozlowski P, Roberts P, Dabora S, Franz D, Bissler J, Northrup H, Au KS, Lazarus R, Domanska-Pakiela D, Kotulska K, Jozwiak S, Kwiatkowski DJ. Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 2007, 121(3-4):389-400.
• King TM, Au KS, Kirkpatrick TJ, Fletcher JM, Townsend I, Tyerman GH, Shimmin LC, Northrup H. The Impact of BRCA1 on Spina Bifida Meningomyelocele Lesions. Ann Hum Genet 2007; 71(Pt 6):719-728.
• Woerner AC, Au KS, Williams AT, Harris PC, Northrup H: Tuberous sclerosis complex and polycystic kidney disease: an exception to the contiguous gene syndrome. Genet in Med 2006, 8(3):197-198.
• Northrup H, Kirkpatrick TJ, Volcik KA, Fletcher JM, Townsend IT, Blanton SH, Tyerman GH, Villarreal G, King TM: Promotor genotype of the platelet derived growth factor receptor alpha gene shows population stratification but not associated with spina bifida meningomyelocele. Am J Med Genet 2005, 139A(3):194-198.
• Au KS, Williams AT, Gambello MJ, Northrup H: Molecular genetic basis of tuberous sclerosis complex: from bench to bedside. J Child Neurol 2004, 19:699-709.

Location & Contact

6431 Fannin Street
MSB 3.020
Houston, Texas 77030
713-500-5757 (Voice)

Faculty Biography

• Dr. Kit Sing (Paul) Au, Ph.D.
  Assistant Professor and Division Head
• Department of Pediatrics
  Division of Genetics
• University of Texas-Houston Medical School
  6431 Fannin Street, MSB-3.518
  Houston, Texas 77030
• phone: (713) 500-5769
  fax: (713) 500-5789
  e-mail: Kit-Sing.Au@ uth.tmc.edu
• Executive Assistant:
  Susan Ramos | 713.500.5663