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.
1. Microdeletions of 3q29 confer high risk for schizophrenia., Mulle, Jennifer Gladys, Dodd Anne F., McGrath John A., Wolyniec Paula S., Mitchell Adele A., Shetty Amol C., Sobreira Nara L. M., Valle D, M Rudd Katharine, Satten Glen, et al., Am J Hum Genet, 2010 Aug 13, Volume 87, Issue 2, p.229-36, (2010)
2. Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism., Mejias, Rebeca, Adamczyk A, Anggono Victor, Niranjan Tejasvi, Thomas Gareth M., Sharma Kamal, Skinner Cindy, Schwartz Charles E., Stevenson Roger E., M Fallin Daniele, et al., Proceedings of the National Academy of Sciences of the United States of America, 2011 Mar 22, Volume 108, Issue 12, p.4920-5, (2011)
3. Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene., Sobreira, Nara L. M., Cirulli Elizabeth T., Avramopoulos Dimitrios, Wohler Elizabeth, Oswald Gretchen L., Stevens Eric L., Ge Dongliang, Shianna Kevin V., Smith Jason P.,Maia Jessica M., et al., PLoS Genet, 2010 Jun, Volume 6, Issue 6, p.e1000991, (2010)
4. Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia., Chen, Pei-Lung, Avramopoulos D, Lasseter Virginia K., McGrath John A., M Fallin Daniele, Liang Kung-Yee, Nestadt G, Feng Ningping, Steel Gary, Cutting Andrew S., et al., American journal of human genetics, 2009 Jan, Volume 84, Issue 1, p.21-34, (2009)
5. PRODH variants and risk for schizophrenia.,Willis, Alecia, Bender Hans Uli, Steel Gary, and Valle D, Amino acids, 2008 Nov, Volume 35, Issue 4, p.673-9, (2008)
6. DNA methylation regulates MicroRNA expression.,Han, Liangfeng, P Witmer Dane, Casey Emily, Valle D, and Sukumar Saraswati, Cancer biology & therapy, 2007 Aug, Volume 6, Issue 8, p.1284-8, (2007)
7. X chromosome cDNA microarray screening identifies a functional PLP2 promoter polymorphism enriched in patients with X-linked mental retardation.,Zhang, Lilei, Jie Chunfa, Obie Cassandra, Abidi Fatima, Schwartz Charles E., Stevenson Roger E., Valle D, and Wang Tao, Genome research, 2007 May, Volume 17, Issue 5, p.641-8, (2007)