Dr. Rubin’s research effort currently focuses on the molecular biology of Familial Dysautonomia (FD). FD, also known as Riley-Day Syndrome or hereditary sensory neuropathy Type III, is an autosomal recessive disorder that affects the development and survival of sensory, sympathetic and some parasympathetic neurons. Individuals with FD are affected with a variety of symptoms which include decreased sensitivity to pain and temperature, cardiovascular instability, recurrent pneumonias, vomiting crises, blood pressure swings, an absence of overflow emotional tears and gastrointestinal dysfunction. This disorder is primarily confined to individuals of Ashkenazi Jewish descent.

In the summer of 2000, Dr. Rubin’s laboratory directed its efforts on identifying the genetic cause of FD. The mutations responsible for FD were found to occur in a gene encoding a protein termed IKAP. These findings were published in the American Journal of Human Genetics [Anderson, S.L., Coli, R., Daly, I.W., Kichula, E.A., Rork, M.J. Volpi, S.A., Ekstein, J. and Rubin, B.Y. (2001) Familial Dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet. 68:753-758]. With the identification of the mutations responsible for FD, genetic testing has been established by several academic and commercial laboratories and couples can now be screened to determine their carrier status and their risk of having children with FD. Large scale studies done to date demonstrate that the carrier frequency for FD is approximately the same as that of Tay Sachs in those of Ashkenazi Jewish descent. It is expected that, with time, there will be a reduction in the number of children born with FD.

While studying cells derived from individuals with FD, members of Dr. Rubin’s laboratory noted that these cells are able to produce some functional IKAP protein. This finding demonstrated that the FD-causing mutation does not completely block the production of the functional IKAP protein. This observation prompted an intense study screening the ability of naturally- derived compounds to modulate the amount of functional IKAP produced in FD-derived cells. After screening hundreds of compounds, these researchers identified two compounds capable of increasing the amount of functional IKAP protein produced in these cells. The two compounds identified are a form of vitamin E called tocotrienol and a chemical component of green tea termed epigallocatechin gallate (EGCG). These findings have since been published: Anderson, S.L., Qiu, J. and Rubin, B.Y. (2003) Tocotrienols induce IKBKAP expression: a possible therapy for Familial Dysautonomia. Biochem. Biophys. Res. Comm. 306:303-309; and Anderson, S.L., Qiu, J., and Rubin, B.Y. (2003) EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with Familial Dysautonomia. Biochem. Biophys. Res. Comm. 310:627-633. The availability of these compounds in health food stores has allowed individuals with FD to take these supplements on a daily basis. Individuals taking these compounds have seen a dramatic reduction in the symptoms associated with FD and have had a dramatic improvement in their quality of life.

Studies underway in the laboratory are aimed at continuing to identify compounds that will increase the amount of functional IKAP produced in individuals with FD and to understand the role IKAP plays in the pathophysiology of FD.

Contact information:

Berish Y. Rubin, Ph.D.
Head, Laboratory for Familial Dysautonomia Research
Fordham University
Larkin Hall Rm. 120
Bronx, New York 10458
Phone: 718-817-3637
Fax: 718-817-2792
Email: rubin@fordham.edu

Sylvia L. Anderson, Ph.D.
Director, Laboratory for Familial Dysautonomia Research
Fordham University
Larkin Hall Rm. 120
Bronx, New York 10458
Phone: 718-817-3650
Fax: 718-817-2792
Email: sanderson@fordham.edu

Anderson, S.L., Coli, R., Daly, I., Kichula, E., Rork, M., Volpi, S., Ekstein, J. and Rubin, B.Y. (2001) Familial dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet. 68: 753-758.

Coli, R., Anderson, S.L., Volpi, S.A. and Rubin, B.Y. (2001) Genomic organization and chromosomal localization of the mouse IKBKAP gene. Gene 279: 81-89.

Anderson, S.L., Qiu, J. and Rubin, B.Y. (2003) Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochem. Biophys. Res. Comm. 306:303-309.

Cuajungco, M.P., Ando, Y., Axelrod, F.B., Biaggioni, I., Goldstein, D.S., Guttmacher, A.E., Gwinn-Hardy, K., Hahn, M.K., Hilz, M.J., Jacob, G., Jens, J., Kennedy, W.R., Liggett, S.B., O'Connor, D.T., Peltzer, S.R., Robertson, D., Rubin, B.Y., Scudder, Q., Smith, L.J., Sonenshein, G.E., Svejstrup, J.Q., Xu, Y. and Slaugenhaupt, S.A. (2003) Hereditary dysautonomias: current knowledge and collaborations for the future. Clin. Auton. Res. 3:180-195.

Anderson, S.L., Qiu, J. and Rubin, B.Y. (2003) EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with Familial Dysautonomia. Biochem. Biophys. Res. Comm. 310:627-633.

Ekstein J., Rubin B.Y., Anderson S.L., Weinstein D.A., Bach G., Abeliovich D., Webb M. and Risch, N. (2004) Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population. Am. J. Med. Genet. 129A:162-4

Anderson, S.L., Ekstein, J., Donnelly, M.C., Keefe, E.M., Toto, N.R., LeVoci, L.A. and Rubin, B.Y. (2004) Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum. Genet. 115:185-90.

Selected Publications:
Gupta, S.L., Rubin, B.Y. and Holmes, S.L. (1979) Interferon action: Induction of specific proteins in mouse and human cells by homologous interferons. Proc. Natl. Acad. Sci. USA 76:4817-4821.

Rubin, B.Y. and Gupta, S.L. (1980) Interferon-induced proteins in human fibroblasts and development of the antiviral state. J. Virol. 34:446-454.

Rubin, B.Y. and Gupta, S.L. (1980) Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents. Proc. Natl. Acad. Sci. USA. 77:5928-5932.

Gupta, S.L., Rubin, B.Y. and Holmes, S.L. (1981). Regulation of interferon action in human fibroblasts: transient induction of specific proteins and amplification of the antiviral response by actinomycin D. Virology 111:331-340.

Rubin, B.Y., Bartal, A.H., Anderson, S.L., Millet, S.K., Hirshaut, Y. and Feit, C. (1983) The anticellular and protein-inducing activities of human gamma interferon preparations are mediated by the interferon. J. Immunol. 130:1019-1020.

Nathan, C.F., Murray, H.W., Wiebe, M.E. and Rubin, B.Y. (1983) Identification of interferon-g as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 158:670-689.

Murray, H.W., Rubin, B.Y. and Rothermel, C.D. (1983) Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes. Evidence that interferon-g is the activating lymphokine. J. Clin. Invest. 72:1506-1510.

Murray, H.W., Rubin, B.Y., Masur, H. and Roberts, R.B. (1984) Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N. Engl. J. Med. 310:883-889.

Rubin, B.Y., Anderson, S.L., Sullivan, S.A.,Williamson, B.D., Carswell, E.A. and Old, L.J. (1985). Purification and characterization of a human tumor necrosis factor from the LuKII cell line. Proc. Natl. Acad. Sci. USA. 82:6637-6641.

Rubin, B.Y., Anderson, S.L., Sullivan, S.A., Williamson, B.D. Carswell, E.A. and Old, L.J.(1985) High affinity binding of 125I-labeled human tumor necrosis factor (LuKII) to specific cell surface receptors. J. Exp. Med. 162:1099-1104.

Rubin, B.Y., Anderson, S.L., Sullivan, S.A., Williamson, B.D., Carswell, E.A. and Old, L.J. (1986) Non-hematopoietic cells selected for resistance to tumor necrosis factor produce tumor necrosis factor. J. Exp. Med. 164:1350-1355.

Broxmeyer, H.E., Williams, D.E., Lu, L., Cooper, S., Anderson, S.L., Beyer, G.S., Hoffman, R. and Rubin, B.Y. (1986) The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-g. J. Immunol. 136:4487-4495.

Rubin, B.Y., Anderson, S.L., Lunn, R.M., Hellermann, G.R., Richardson, N.K. and Smith, L.J. (1988) Production of a monoclonal antibody directed against an interferon-induced 56,000 dalton protein and its use in the study of this protein. J. Virol. 62:1875-1880.

Rubin, B.Y., Anderson, S.L., Lunn, R.M., Richardson, N.K., Hellermann, G.R., Smith, L.J. and Old, L.J. (1988) Tumor necrosis factor and IFN induce a common set of proteins. J. Immunol. 141:1180-1184.

Rubin, B.Y., Anderson, S.L., Hellerman, G.R., Richardson, N.K., Lunn, R.M. and Valinsky, J.E. (1988) The development of antibody to the interferon-induced indoleamine 2,3-dioxygenase and the study of the regulation of its synthesis. J. Interferon Res. 8:691-702.

Rubin, B.Y., Smith, L.J., Hellermann, G.R., Lunn, R.M., Richardson, N.K. and Anderson, S.L. (1988) Correlation between the anticellular and DNA fragmenting activities of tumor necrosis factor. Cancer Res. 48:6006-6010.

Margolis-Nunno, H., Rubin, B.Y., Anderson, S.L., Lunn, R.M., Roy, S.N., Dizik, M.D. and Sen, G.C. (1990) Isolation of cDNA clones for the interferon-induced 67,000 dalton protein: Direct induction of a family of mRNAs by human interferon-a and interferon-g. J. Interferon Res. 10:309-319.

Rubin, B.Y., Anderson, S.L., Xing, L., Powell, R.J., and Tate, W.P. (1991) Interferon induces tryptophanyl tRNA synthetase expression in human fibroblasts. J. Biol. Chem. 266:24245-24248.

Lou, J., Anderson, S.L., Xing, L. and Rubin, B.Y. (1994) Suppression of mitochondrial function in cells responding to the anticellular action of interferon. J. Interferon Res. 14:33-40.

Anderson, S.L., Shen, T., Lou, J. Xing, L., Blachere, N.E., Srivastava, P.K., and Rubin, B.Y. (1994) The endoplasmic reticular heat shock protein gp96 is transcriptionally up-regulated in interferon-treated cells. J. Exp. Med. 180:1565-1569.

Shen, T., Anderson, S.L. and Rubin, B.Y. (1995) Use of alternative polyadenylation sites in the synthesis of mRNAs encoding the interferon-induced tryptophanyl tRNA synthetase. Gene 179/2:225-229.
Anderson, S.L., Carton, J.M., Lou, J., Xing, L. and Rubin, B.Y. (1999) Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. Virology 256:8-14.

Anderson, S.L., Carton, J.M, Zhang, X. and Rubin, B.Y. (1999) Genomic organization and chromosomal localization of a new member of the murine interferon-induced guanylate binding protein family. J. Interferon & Cytokine Res. 19:487-494.