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James Friedman, Ph.D.

James Friedman, Ph.D.

​Retinal degenerative diseases, such as retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are a leading cause of inherited blindness. Although substantial progress has been made in the discovery of retinal disease genes, much work remains to elucidate the genetic and molecular causes of RP and LCA.

Dr. Friedman's research has followed two broad themes, forward genetics of mouse and human retinal diseases, and functional studies of identified genes. He has worked on two mouse models of retinal disease, rd3 and rd11. The retinal degeneration 3 (rd3) mice are one of the oldest known strains of retinal degeneration. The mice consist of 5 lines that are descendants of the original mice captured in 1969. Through a candidate gene approach, he identified the gene (3322402L07Rik, now Rd3) responsible for this phenotype. A large human retinopathy disease screen resulted in the discovery of two siblings with Leber Congenital Amaurosis containing mutations in the RD3 gene (Friedman et al. AJHG 2006). The rd11 mice exist as two strains of independent origin, rd11 and B6-JR2845. The two strains share similar phenotypes, but have different causative mutations. Mutations in Lpcat1, a gene encoding the lipid remodeling enzyme lysophosphatidylcholine acyltransferase 1 is responsible for the phenotype observed in both strains of mice (Friedman et al. PNAS 2010).

In human genetic studies and in collaboration with Dr. Sten Andreasson, Dr. Friedman performed linkage analysis on a large Scandinavian family with a milder form of RP and determined that a mutation in exon 6 of Kelch-like 7 (KLHL7) was responsible for disease in this family. A larger mutation screen (502 probands) performed with collaborators in the U.K., Texas, Michigan and Scandinavia identified six families with three mutations in KLHL7. KLHL7 belongs to a family containing characteristic protein motifs (BTB, Back, Kelch) that have been associated with the ubiquitin proteasomal system that bridge between E3 ubiquitin-ligases and their substrates. Based on this relationship, we hypothesize that KLHL7 also plays a role in ubiquitination. Structural modeling of KLHL7 suggested that each mutation identified (S150N, A153T, A153V) fills a cleft between two helices of the Back domain and may affect KLHL7’s function (Friedman et al. AJHG 2009).

Dr. Friedman is currently following up on RD3 and KLHL7 and is exploring why these two proteins, when mutated, lead to retinal disease. He is also interested in using next-generation sequencing to uncover novel retinal disease genes.

Publications
 
  1. Friedman, J.S., Chang, B., Krauth, D.S., Lopez, I., Waseem, N.H., Hurd, R.E., Feathers, K.L., Branham, K.E., Shaw, M., Thomas, G.E., Brooks, M.J., Liu, C., Bakeri, H.A., Campos, M.M., Maubaret, C., Webster, A.R., Rodriguez, I.R., Thompson, D.A., Koenekoop, R.K., Bhattacharya, S.S., Heckenlively, J.R., and Swaroop, A. Loss of lysophosphatidylcholine acyltransferase 1 (LPCAT1) leads to photoreceptor degeneration in rd11 mice. (2010) Proceedings of the National Academy of Sciences of the U.S.A. Aug 31;107(35):15523-8. Epub 2010 Aug 16.
  2. Hugosson, T., Friedman, J.S., Ponjavic, V., Abrahamson, M., Swaroop, A., and Andréasson, S. Phenotype associated with mutation in the recently identified autosomal dominant retinitis pigmentosa KLHL7 gene. (2010) Archives of Ophthalmology Jun;128(6):772-8.
  3. Permanyer, J., Navarro, R., Friedman, J.S., Pomares, E., Castro-Navarro, J., Marfany, G., Swaroop, A., and Gonzàlez-Duarte, R. A novel mutation in PROM1 that results in nonsense mediated decay causes autosomal recessive Retinitis Pigmentosa with early macular affectation. (2010) Investigative Ophthalmology and Visual Science May;51(5):2656-63. Epub 2009 Dec 30.
  4. Friedman, J.S., Ray, J.W., Waseem, N., Johnson, K., Brooks, M.J., Hugosson, T., Breuer, D., Branham, K.E., Krauth, D.S., Bowne, S.J., Sullivan, L.S., Ponjavic, V., Gränse, L., Khanna, R., Trager, E.H., Gieser, L.M., Hughbanks-Wheaton, D., Cojocaru, R.I., Ghiasvand, N.M., Chakarova, C.F., Abrahamson, M., Göring, H.H.H., Webster, A.R., Birch, D.G., Abecasis, G.R., Fann, Y., Bhattacharya, S.S., Daiger, S.P., Heckenlively, J.R., Andréasson, S., and Swaroop, A. Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa. (2009) American Journal of Human Genetics Jun;84(6):792-800.
  5. Kukekova, A.V., Goldstein, O., Johnson, J.L., Richardson, M.A., Pearce-Kelling, S.E., Swaroop, A., Friedman, J.S., Aguirre, G.D., and Acland, G.M. Canine RD3 mutation establishes rod-cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3. (2009) Mammalian Genome. Feb;20(2):109-23.
  6. Chakarova, C.F., Papaioannou, M.G., Khanna, H., Lopez, I., Waseem, N., Shah, A., Theis, T., Friedman, J., Maubaret, C., Bujakowska, K., Veraitch, B., Abd El-Aziz, M.M., Prescott, de Q., Parapuram, S.K., Bickmore, W.A., Munro, P.M., Gal, A., Hamel, C.P., Marigo, V., Ponting, C.P., Wissinger, B., Zrenner, E., Matter, K., Swaroop, A., Koenekoop, R.K., and Bhattacharya, S.S. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. (2007) American Journal of Human Genetics Nov;81(5):1098-103.
  7. Kanda, A., Friedman, J.S., Nishiguchi, K.M., and Swaroop, A. Retinopathy mutations in the Maf-family bZIP protein NRL alter phosphorylation and transcriptional activity. (2007) Human Mutation Mar 2;28(6):589-598.
  8. Merienne, K., Friedman J., Akimoto, M., Abou-Sleymane, G., Weber, C., Swaroop, A., and Trottier, Y. Preventing Polyglutamine-Induced Activation of c-Jun Delays Neuronal Dysfunction in a Mouse Model of Sca7 Retinopathy. (2007) Neurobiology of Disease Mar;25(3):571-81.
  9. Friedman, J.S., Chang, B., Kannabiran, C.K., Chakarova, C., Singh, H.P., Jalali, S., Hawes, N.L., Branham, K., Othman, M., Filippova, E., Thompson, D.A., Webster, A.R., Andréasson, S., Jacobson, S.G., Bhattacharya, S.S., Heckenlively, J.R., and Swaroop, A. Premature Truncation of a Novel Protein, RD3, Exhibiting Sub-Nuclear Localization is Associated with Retinal Degeneration. (2006) American Journal of Human Genetics Dec;79(6):1059-70. Erratum in: Am J Hum Genet. 2007 Feb;80(2):388.
  10. Khanna, H., Akimoto, M., Siffroi-Fernandez, S., Friedman, J.S., Hicks, D., and Swaroop, A. Retinoic Acid Regulates the Expression of Photoreceptor Transcription Factor NRL. (2006) Journal of Biological Chemistry Sep 15;281(37):27327-34.
  11. Nishiguchi, K.M., Friedman, J.S., Sandberg, M.A., Swaroop, A., Berson, E.L., and Dryja, T.P. Recessive NRL Mutations in Patients with Clumped Pigmentary Retinal Degeneration and Relative Preservation of Blue Cone Function. (2004) Proceedings of the National Academy of Sciences of the U.S.A. Dec 21;101(51):17819-24.
  12. Friedman, J.S*., Khanna, H*., Swain, P.K., DeNicola, R., Cheng, H., Mitton, K.P., Weber, C.H., Hicks, D., and Swaroop, A. The Minimal Transactivation Domain of the Basic Motif-Leucine Zipper Transcription Factor NRL Interacts with TATA-Binding Protein. (2004) Journal of Biological Chemistry Nov 5;279(45):47233-41. *Co-first authors
  13. Yu, J., He, S., Friedman, J.S., Akimoto, M., Ghosh, D., Mears, A.J., Hicks, D., and Swaroop, A. Altered Expression of Genes of the Bmp/Smad and Wnt/Calcium Signaling Pathways in the Cone-only Nrl-/- Mouse Retina, Revealed by Gene Profiling Using Custom cDNA Microarrays. (2004) Journal of Biological Chemistry Oct 1;279(40):42211-20.
  14. Yoshida, S., Mears, A.J., Friedman, J.S., Carter, T., He, S., Oh, E., Jing, Y., Farjo, R., Fleury, G., Barlow, C., Hero, A.O., and Swaroop, A. Expression Profiling of the Developing and Mature Nrl-/- Mouse Retina: Identification of Retinal Disease Candidates and Transcriptional Regulatory Targets of Nrl. (2004) Human Molecular Genetics Jul 15;13(14):1487-503.
  15. Friedman, J.S., Faucher, M., Hiscott, P., Biron, V.L., Malenfant, M., Turcotte, P., Raymond, V., and Walter, M.A. Protein Localization in the Human Eye and Genetic Screen of Opticin. (2002) Human Molecular Genetics 11(11):1333-1342.
  16. Friedman, J.S., Koop, B., Raymond, V., and Walter, M.A. Isolation of a Ubiquitin-Like (UBL5) Gene from a Screen Identifying Highly Expressed and Conserved Iris Genes. (2001) Genomics Jan 15;71(2):252-5.
  17. Friedman, J.S., Ducharme, R., Raymond, V., and Walter, M.A. A Novel Leucine-Rich Protein Isolated Using Differential Selection from Human Iris. (2000) Investigative Ophthalmology and Visual Science 41(8):2059-2066.
  18. Tucker, J.E., Winkfein, R.J., Murthy, S.K., Friedman, J.S., Walter, M.A., Demetrick, D.J., and Schnetkamp, P.P.M. Chromosomal Localization and Genomic Organization of the Human Retinal Rod Na-Ca+K Exchanger. (1998) Human Genetics 103:411-414.
 
Chapters/Reviews:
 
  1. Friedman, J.S., and Walter, M.A. Biomedicine: Under Pressure. (2002) Science Feb 8;295(5557):983-4.
  2. Friedman, J.S., and Walter, M.A. Use of Radiation Hybrid Panels to Map Genetic Loci. (2001) Molecular Biotechnology 19(2):205-10.
  3. Friedman, J.S., and Walter, M.A. Glaucoma Genetics, Present and Future. (1999) Clinical Genetics 55:71-79.