Arthur L. Beaudet, M.D.
Professor and Chairman, Department of Molecular and Human Genetics
Professor, Departments of Pediatrics and Molecular and Cellular Biology
B.S., College of the Holy Cross
M.D., Yale University School of Medicine
Resident in Pediatrics, John Hopkins Hospital
Postdoc, National Institutes of Health
Our laboratory is studying the role of epigenetics in human disease with particular emphasis on genomic imprinting and its role in Prader-Willi syndrome (PWS), Angelman syndrome (AS), and autism. Genomic imprinting is the phenomenon of differential expression of the two alleles at an autosomal locus based on their parent of origin; usually one allele is expressed and the other silenced. PWS and AS are distinct human disorders characterized by neurobehavioral abnormalities and mental retardation. They are caused by deficiency of paternally (PWS) or maternally (AS) expressed genes within chromosome 15q11-q13. Our laboratory has contributed to identification of molecular defects causing PWS and AS, identified the UBE3A locus encoding E6-AP ubiquitin-protein ligase as the AS gene, and made numerous mouse models related to PWS and AS. The molecular findings in AS and evidence that genomic imprinting of 15q11-q13 also plays a role in autism have led us to propose a mixed epigenetic and genetic and mixed de novo and inherited model for oligogenic inheritance of autism with a limited role for the AS gene, UBE3A. This proposes a radically different model with one or a few major genes causing autism. In other work on genomic imprinting, we have proposed a "rheostat model" suggesting that imprinted genes have evolved to be hypervariable for their level of expression; we propose that this hypervariability in combination with haploid selective advantage allows a rapid and reversible form of imprinting-related evolution affecting growth, behavior, and perhaps other traits. Our current work is aimed at 1) unraveling the epigenetic and genetic basis of autism; 2) identifying the specific genes causing PWS; 3) attempting to increase the leakiness of silencing of the paternal copy of the AS gene as a treatment for AS; 4) using genetic screens in mice, both in vivo and in ES cells, to probe the biology of genomic imprinting; and 5) rigorously testing the rheostat model for genomic imprinting.
In collaboration with Dr. Philip Ng, the laboratory also is active in preclinical studies of helper-dependent adenoviral (HD-Ad) vectors. A variety of strategies in baboons have allowed high efficiency expression in hepatocytes while minimizing systemic toxicity. Recent studies of airway delivery in animals are very encouraging for gene therapy in cystic fibrosis. Two INDs are being prepared to conduct clinical trials in Crigler-Najjar syndrome and cystic fibrosis; trials in hemophilia are planned as well.
Brunetti-Pierri N, Ng T, Iannitti DA, Palmer DJ, Beaudet AL, Finegold MJ, Carey KD, Cioffi WG, Ng P (2006). Improved hepatic transduction, reduced systemic vector dissemination, and long-term transgene expression by delivering helper-dependent adenoviral vectors into the surgically isolated liver of nonhuman primates. Hum. Gene Ther. 17: 391-404.
Van den Veyver IB, Beaudet AL (2006). Comparative genomic hybridization and prenatal diagnosis. Curr. Opin. Obstet. Gynecol. 18:185-191.
Wu MY, Chen KS, Bressler J, Hou A, Tsai TF, Beaudet AL (2006). Mouse imprinting defect mutations that model Angelman syndrome. Genesis 44: 12-22.
Cheung SW, Shaw CA, Yu W, Li J, Ou Z, Patel A, Yatsenko SA, Cooper ML, Furman P, Stankiewicz P, Lupski JR, Chinault AC, Beaudet AL (2005). Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet. Med. 7: 422-432. Erratum in: Genet. Med. 7: 478.
Brunetti-Pierri N, Nichols TC, McCorquodale S, Merricks E, Palmer DJ, Beaudet AL, Ng P (2005). Sustained phenotypic correction of canine hemophilia B after systemic administration of helper-dependent adenoviral vector. Hum. Gene Ther. 16: 811-820.
Jiang YH, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD, Liu Q, Shaffer LG, Schroer RJ, Stockton DW, Spielman RS, Stevenson RE, Beaudet AL (2004). A Mixed Epigenetic/Genetic Model for Oligogenic Inheritance of Autism with a Limited Role for UBE3A. Am. J. Med. Genet. A. 131: 1-10.
Jiang YH, Bressler J, Beaudet AL (2004). Epigenetics and Human Disease. Annu. Rev. Genomics Hum. Genet. 5: 479-510.
For more publications, see listing on PubMed.
Arthur L. Beaudet, M.D.
Henry and Emma Meyer Professor and Chair
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
Telephone: (713) 798-4795
Fax: (713) 798-7773