David Valle, M.D., Ph.D.Image

Henry J. Knott Professor and Director, Institute of Genetic Medicine

Professor of Pediatrics, Ophthalmology, Molecular Biology and Genetics, and Institute of Genetic Medicine

Director of Predoctoral Training Program in Human Genetics

Director of Center of Inherited Disease Research

Contact Information

Room 519, Broadway Research Building
410-955-4260
410-955-7397 (Fax)
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Research Interests

My research interests involve clinical, biochemical, molecular and therapeutic aspects of human genetic diseases. Currently, we focus on three related areas of investigation. The first involves molecular, biochemical and structural studies of the enzymes of proline and ornithine metabolism including ornithine-delta-aminotransferase (OAT). Deficiency of OAT causes a blinding chorioretinal degeneration known as gyrate atrophy of the choroid and retina (GA). The challenge now is to understand the pathophysiology of the retinal degeneration and how to prevent it. To this end we have produced a knockout mouse deficient in OAT and have show that it develops a retinal degeneration. We are using this model to understand why the retina is involved and to test various experimental therapies for GA.

A second research area involves identification of genes that are expressed preferentially or exclusively in human retina. We are interested in the biology of their protein products as well as their possible role in retinal degenerations. One example is PHR1, a gene expressed at very high levels in photoreceptors and other primary sensory neurons for which we have produced a knockout mouse.

Third, we are interested in the genes encoding the matrix enzymes and membrane proteins of the peroxisome, a ubiquitous subcellular organelle whose protein components participate in numerous metabolic pathways. Using a variety of strategies, we have cloned several of these and are examining their role in genetic disorders of peroxisomal biogenesis (e.g. Zellweger syndrome) and function (e.g. X-linked adrenoleukodystrophy). 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.

Lastly, we have taken advantage of the recently available human genome sequence to collect and analyze all the genes known to be involved in human genetic disease. In a search for general principles of disease, we are correlating the function of the protein products of these disease genes with various aspects of the disease phenotypes.

Selected Publications

  • Wang T., Steel G., Milam A.H. and Valle D.: Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina. Proc Natl Acad Sci USA 97: 1224-1229, 2000.
  • Baumgartner M.R., Almashanu S., Suormala T., Obie C., Cole R.N., Morton D.H., Packman S., Baumgartner E.R. and Valle D.: The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency. J Clin Invest 107: 495-504, 2001.
  • Jimenez-Sanchez G., Childs B. and Valle D.: Human disease genes: Protein function and clinical phenotype. Nature 409: 853-855, 2001.
  • Fallin M.D., Lasseter V.K., Wolyniec P.S., McGrath J.A., Nestadt G., Valle D., Liang K-Y and Pulver A.E.: Genome-wide linkage scan for schizophrenia susceptibility loci among Ashkenzai Jewish families shows evidence for linkage on chromosome 10q22. Am J Hum Genet 73: 601-611, 2003.
  • Weller S., Gould S.J. and Valle D.: Peroxisome biogenesis disorders. Annu Rev Genomics & Hum Genet 4: 165-211, 2003.
  • Xu S., Wang Y., Zhao H., Xiong W., Yau K-Y, Hiel H., Glowatzki E., Ryugo D. and Valle D.: PHR1, a PH domain-containing protein, expressed in primary sensory neurons. Mol Cell Biol 24: 9137-9151, 2004.
  • Fallin M.D., Lasseter V.K., Wolyniec P.S., McGrath J.A., Nestadt G., Valle D., Liang K-Y. and Pulver A.E.: Genomewide linkage scan for bipolar-disorder susceptibility loci among Ashkenazi Jewish families. Am J Hum Genet 75: 204-219, 2004.
  • Baumgartner M.R., Dantas M.F., Suormala T., Almashanu S., Giunta C., Friebel D., Gebhardt B., Fowler B., Hoffmann G.F, Baumgartner E.R. and Valle D.: Isolated 3-methylcrotonyl-CoA carboxylase deficiency: Evidence for an allele-specific dominant negative effect and response to biotin therapy. Am J Hum Genet 75: 790-800, 2004
  • Weller S., Cajigas I., Morrell J., Obie C., Steel G., Gould S.J. and Valle D.: Alternative splicing suggests extended function of PEX26 in peroxisome biogenesis. Am J Hum Genet 76: 987-1007, 2005.
  • Bender H., Almashanu S., Steel G., Hu C-A., Lin W-W, Willis A., Pulver A., and Valle D.: Functional consequences of PRODH missense mutations. Am J Hum Genet 76: 409-420, 2005.

Book Chapters:
  • Phang JM, Hu C-A, Valle D: Disorders of proline and hydroxyproline metabolism. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AR, Sly W, Valle D (eds), McGraw-Hill, New York, pp 1821-1838, 2001.
  • Beaudet AL, Scriver CR, Sly WS, Valle D: Genetics, biochemistry and molecular basis of variant human phenotypes. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AR, Sly W, Valle D (eds), McGraw-Hill, New York, pp 3-45, 2001.
  • Jimenez-Sanchez G, Childs B, Valle D: The effect of Mendelian disease on human health. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AR, Sly W, Valle D (eds), McGraw-Hill, New York, pp 167-174, 2001.
  • Valle D, Simell O: The hyperornithinemias. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AR, Sly W, Valle D (eds), McGraw-Hill, New York, pp 1857-1896, 2001.
  • Childs B, Valle D, Jimenez-Sanchez G: The inborn error and biochemical individuality. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AR, Sly W, Valle D (eds), McGraw-Hill, New York, pp 155-166, 2001.
  • Gould SJ, Raymond G, Valle D: The peroxisome biogenesis disorders. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AR, Sly W, Valle D (eds), McGraw-Hill, New York, pp 3181-3218, 2001.
  • Treacy EP, Valle D, Scriver CR: Treatment of genetic disease. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR, Beaudet AR, Sly W, Valle D (eds), McGraw-Hill, New York, pp 175-192, 2001.
 
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