KANG ZHANG, M.D., Ph.D.

LAB WEBSITE

B.S. 1984, Sichuan University, China
M.D. 1995, Harvard Medical School-M.I.T.
PhD. 1991, Harvard University

RESEARCH:

The overall goal of my laboratory is to gain insights into molecular mechanisms of macular degeneration. We are taking two approaches to uncover key genes and pathways in macular degeneration. First, we will continue to employ juvenile macular dystrophies as a model system. Juvenile macular dystrophies, such as Stargardt's macular dystrophy (the most common form of juvenile macular degeneration) and dominant drusen, share many important clinical and histopathological features with AMD, yet they are much more easily studied by standard genetic and molecular methods. Such an approach has been fruitful, as we have mapped several genes for Stargardt's macular dystrophy and dominant drusen by genetic linkage analysis. Using a positional cloning method, we identified a novel gene, ELOVL4 and showed that a 5-bp deletion in ELOVL4 segregated in all affected patients of five large families with STGD3 (MIM 600110, an autosomal dominant form of Stargardt macular dystrophy).

Macular degeneration is a heterogeneous group of disorders characterized by progressive loss of central vision resulting from the degeneration of photoreceptors in the central part of the retina, the macula. Age-related macular degeneration (AMD), the most common form of the disease, is the leading cause of irreversible blindness in the United States and in many developed countries throughout the world. The overall goal of my laboratory is to gain inssights into molecular mechanisms of macular degeneration. We are taking two approaches to uncover key genes and pathways in macular degeneration.

First, we will continue to employ juvenile macular dystrophies as a model system. Juvenile macular dystrophies, such as Stargardt's macular dystrophy (the most common form of juvenile macular degeneration) and dominant drusen, share many important clinical and histopathological features with AMD, yet they are much more easily studied by standard genetic and molecular methods. Such an approach has been fruitful, as we have mapped several genes for Stargardt's macular dystrophy and dominant drusen by genetic linkage analysis. Using a positional cloning method, we identified a novel gene, ELOVL4 and showed that a 5-bp deletion in ELOVL4 segregated in all affected patients of five large families with STGD3 (MIM 600110, an autosomal dominant form of Stargardt macular dystrophy). ELOVL4 demonstrated photoreceptor specific expression in the eye and encoded a putative transmembrane protein with similarities to the ELO family involved in elongation of very long chain polyunsaturated fatty acids. ELOVL4 is the first gene involved in the biosynthesis of fatty acids implicated in macular degeneration. We are currently using in vitro cell culture and in vivo transgenic and knockout systems to study the role of normal and mutant ELOVL4 gene in the synthesis of very long chain fatty acids as well as elucidate the effect of mutations of ELOVL4 on the function of retinal photoreceptor cells. We are in the process of cloning several other genes for macular degeneration

Second, we are taking a direct approach to study AMD. We are conducting genome-scans to map gene(s) in large families with an autosomal dominant form of AMD. In addition, taking advantage of tremendous genetic resources at the University of Utah, particularly the Mormon population databases of 1.3 million in size derived from 5500 founders, we are using both parametric and non-parametric methods to map and identify genes for complex trait diseases, such as age-related macular degeneration.

SELECT PUBLICATIONS:

Zhang, K., Chaillet, R., Perkins, L.A., Halazonetis, T. and Perrimon, N. (1990). The Drosophila homolog of the mammalian jun oncogene is expressed during embryonic development and activates transcription in mammalian cells. Proc. Natl. Acad. Sci. USA. 87, 6281.

Zhang, K., Smouse, D. and Perrimon, N. (1991). The crooked neck gene of Drosophila contains a motif found in a family of yeast cell cycle genes. Genes & Development 5, 1080.

Rutledge, B.,* Zhang, K.*, Bier, E., Jan, Y. and Perrimon, N. (1992) The Drosophila spitz gene encodes a putative EGF-like growth factor involved in dorsal-ventral axis formation and neurogenesis. Genes & Dev. 6, 1503. * co-first authors

Kniazeva, M., Chiang, M.F., Morgan, B., Anduze, A.L., Zack, D.J., Han, M., and Zhang. K. (1999). A new locus for autosomal dominant Stargardt-like disease maps to chromosome 4. American Journal Human Genetics. 64, 1394

Zhang, K., Kniazeva, M., Han, M., Dean, M., Allikmets, R. (1999). The ABCR gene in dominant and recessive Stargardt's disease: a genetic pathway in macular degeneration. Genomics 60, 234.

Zhang, K., Kniazeva, M., Han, M., Li, W., Yu, Z., Yang, Z., Li, Y., Metzker, M. L., Allikmets, R. L., Zack, D. J., Kakuk, L. E., Lagali, P. S., Wong, P. W., MacDonald, I. M., Sieving, P. A., Figueroa, D., Austin, C. P., Robert J. Gould, R. J., Ayyagari, R., Petrukhin, K. (2001). A five base-pair deletion in the ELOVL4 gene is associated with two related forms of autosomal dominant macular dystrophy. Nature Genetics 27, 89.

Identification and functional consequences of a new mutation (E155G) in GCAP1 causing autosomal dominant cone dystrophy. Wilkie, S. E., Li, Y., Deery , E. C., Newbold, R., Garibaldi, D. C., Bateman, J. B., Zhang, H., Zack, D. J., Bhattacharya, S. S., Warren, M. J., Hunt, D. M., and Zhang, K. (2001). Am J Human Genetics 69, 471.

Zhang, K., Garibaldi, D., Li, Y., Green, W. R., Zack, D.J. (2002). Butterfly-shaped pattern dystrophy: A genetic, clinical and histopathologic report. Arch. Ophthalmology 120, 485.

Yang, Z., Peachey, N.S., Moshfeghi, D.M., Chorich, L., Thirumalaichary, S., Shugart, Y., Fan, K., and Zhang, K. (2002). Mutations in the RPGR gene cause X-linked cone dystrophy. Human Molecular Genetics 11, 605.