In the broadest sense, my research interests include understanding all aspects of the role of genetic factors in human health and disease. In particular, our studies involve clinical, biochemical, molecular and therapeutic aspects of specific human genetic diseases as well as more global studies of the network interactions and consequences of the genes and proteins implicated in human disease.
In the past, our lab has focused primarily on rare monogenic disorders including inborn errors of amino acid metabolism as well as various human retinal degenerations. For example, we have conducted extensive molecular, biochemical and structural studies of the enzymes of proline and ornithine metabolism defining the biochemical and molecular bases of several. Most notably, we showed that deficiency of ornithine-delta-aminotransferase (OAT) causes a blinding, chorioretinal degeneration known as gyrate atrophy of the choroid and retina (GA). We also produced a knockout mouse deficient in OAT, showed that it develops a retinal degeneration and used this model to develop and validate treatments. Similarly, we are interested in inborn errors of biogenesis and function of the peroxisome, a ubiquitous sub-cellular organelle whose protein components participate in numerous metabolic pathways. Using a variety of strategies, we identified the genes responsible for several (>10) genetic disorders of peroxisomal biogenesis (e.g. Zellweger syndrome). We also have a special interest in peroxisomal ABC transporters and have produced knockout mice for the genes encoding some of these to elucidate the function of these transporters and their role in human genetic disease.
Recently, we have focused most of our efforts on understanding the genetic contribution to neuropsychiatric disease, especially schizophrenia. Working together with our collaborators Ann Pulver, Dimitri Avramopoulos and Gerry Nestadt, we have utilized a variety of whole genome approaches to search for genetic variants contributing risk for these disorders. Currently we are performing extensive studies of the genes in 10q22-23 and 8p21; we have found both linkage and association evidence for one or more schizophrenia susceptibility genes in both these regions. Our studies include extensive high throughput genotyping and sequencing, functional evaluation of coding variants and variants in candidate regulatory sequences and development and characterization of mouse models for the strongest candidates. The overall all goals of these studies are to identify the genes and the causative variants contributing risk and to use this information to identify key biological systems involved in the causation and pathophysiology of these disorders. We will use this information to search for additional risk genes and environmental variables as well as for the rational development of therapies.
Mejias R, Adamczyk A, Anggono V, Niranjan T, Thomas GM, Sharma K, Skinner C, Schwartz CE, Stevenson RE, Fallin MD, Kaufmann W, Pletnikov M, Valle D, Huganir RL, Wang T. "Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism." Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4920-5.
Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC, Sobreira NL, Valle D, Rudd MK, Satten G, Cutler DJ, Pulver AE, Warren ST. "Microdeletions of 3q29 confer high risk for schizophrenia." Am J Hum Genet. 2010 Aug 13;87(2):229-36.
Sobreira NL, Cirulli ET, Avramopoulos D, Wohler E, Oswald GL, Stevens EL, Ge D, Shianna KV, Smith JP, Maia JM, Gumbs CE, Pevsner J, Thomas G, Valle D, Hoover-Fong JE, Goldstein DB. "Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene." PLoS Genet. 2010 Jun 17;6(6):e1000991.
Chen PL, Avramopoulos D, Lasseter VK, McGrath JA, Fallin MD, Liang KY, Nestadt G, Feng N, Steel G, Cutting AS, Wolyniec P, Pulver AE, Valle D. "Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia." Am J Hum Genet. 2009 Jan;84(1):21-34. doi: 10.1016/j.ajhg.2008.12.005.
Willis A, Bender HU, Steel G, Valle D. "PRODH variants and risk for schizophrenia." Amino Acids. 2008 Nov;35(4):673-9. doi: 10.1007/s00726-008-0111-0. Epub 2008 Jun 5.
Han L, Witmer PD, Casey E, Valle D, Sukumar S. "DNA methylation regulates MicroRNA expression." Cancer Biol Ther. 2007 Aug;6(8):1284-8. Epub 2007 May 24.
Zhang L, Jie C, Obie C, Abidi F, Schwartz CE, Stevenson RE, Valle D, Wang T. "X chromosome cDNA microarray screening identifies a functional PLP2 promoter polymorphism enriched inpatients with X-linked mental retardation." Genome Res. 2007 May;17(5):641-8. Epub 2007 Apr 6.