Prof. Mia Horowitz

My lab is involved in two projects:

1. The molecular biology underlying Gaucher's disease:  Gaucher disease is a genetic autosomal recessive disease caused by decreased activity of the lysosomal enzyme glucocerebrosidase. Since the enzyme has an activator, saposin C, encoded by the prosaposin gene, mutations within the glucocerebrosidase gene or the prosaposin gene lead to Gaucher disease. We study the regulation of expression of the genes, their interactions with other proteins and mutations in Gaucher disease. We also created a prosaposin knock-out model missing one protein isoform.
2. The role of the EH proteins in endocytosis and intracellular trafficking:  We discovered a family of proteins that participate in endocytosis and intracellular trafficking, designated EHDs (EH-domain containing).  We test their interactions with other proteins known to be involved in trafficking processes, study their biochemical characteristics and follow their localization.  We are also creating knock-out animals, not expressing the EHDs.

R. Rotem-Yehudar, E. Galperin ,.M. Horowitz. Association of insulin like growth factor 1 receptor with EHD1 and SNAP29. J. Biol. Chem. Vol. 276, 2001 (pp.33054-33060)

E. Hazkani-Covo, N. Altman, M. Horowitz, D. Grauer. The evolutionary history of prosaposin: two successive tandem-duplication events gave rise to the four saposin domains in vertebrates. J. Mol. Evol. Vol. 54, 2002 (pp.30-34).

E. Galperin, S. Benjamin, D. Rapaport, R. Rotem-Yehudar, M. Horowitz. EHD3 - a protein that resides in recycling vesicular and tubular membrane structures and interacts with EHD1. Traffic. Vol. 3, 2002 (pp. 575-89).

K. Hodanova, Z. Malkova, M. Horowitz, M. Hrebicek. Transient expression of wild-type and mutant glucocerebrosidases in hybrid vaccinia expression system. Eur J Hum Genet. Vol. 11, 2003 (pp. 369-374).

A.H. Futerman, J.L. Sussman, M. Horowitz, I. Silman, A. Zimran. New directions in the treatment of Gaucher disease. Trends in Pharmacological Science, Vol. 25, 2004 (pp. 147-151).

T. Cohen, L. Ravid, N. Altman, L. Madar-Shapiro, A. Fein, M. Weil, M. Horowitz. Conservation of expression and alternative splicing in the prosaposin gene, Molecular Brain Research Vol. 129, 2004 (pp. 8-19).

T. Cohen, W. Auerbach, L. Ravid, J. Bodennec, A. Fein, A.H. Futerman, A.L. Joyner, M. Horowitz. The exon 8 containing prosaposin splice variant is dispensable for mouse development, lysosomal function and secretion. Mol. Cell. Biol. Vol. 25, 2005 (pp. 2431-2440).

I. Ron, A. Dagan, S. Gatt, M. Pasmanik-Chor, M. Horowitz. Use of fluorescent substrates for characterization of Gaucher disease mutations. Blood Cells Mol Dis. 2005 35 (pp. 57-65).

E. Sprecher, A. Ishida-Yamamoto, M. Mizrahi-Koren, D. Rapaport, D. Golsher, M. Indelman, O. Topaz, I. Chefetz, H. Keren, T.J. O’Brien, D. Bercovich, S. Shalev, D. Geiger, R. Bergman, M. Horowitz, H. Mandel. A mutation in SNAP29 , coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichtyosis and palmoplantar keratoderma. Am J Hum Genet. 2005 77 (pp. 242-251).

I. Ron, M. Horowitz. ER retention and degradation as the molecular mechanism underlying Gaucher disease heterogeneity. Hum. Mol. Gen. 2005 15 (pp. 2387-2398).

E. Sprecher, A. Ishida-Yamamoto, M. Mizrahi-Koren, D. Rapaport, D. Golsher, M. Indelman, O. Topaz, I. Chefetz, H. Keren, T.J. O’Brien, D. Bercovich, S. Shalev, D. Geiger, R. Bergman, M. Horowitz, H. Mandel. A mutation in SNAP29 , coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichtyosis and palmoplantar keratoderma. Am J Hum Genet. 2005 77 (pp. 242-251).

D. Rapaport, W. Auerbach, N. Naslavsky, M. Pasmanik-Chor, E. Galperin, E. Fein, S. Kaplan, A. Joyner, M. Horowitz. Recycling to the plasma membrane is attenuated in EHD1 knockout mice. Traffic 2006 7 (pp 52-60).

Mandel H, Sprecher E, Rapaport D, Horowitz M. SNAP29 and cerebral dysgenesis, neuropathy, ichthyosis and palmoplantar keratoderma syndrome. In: Inborn Errors of Development. CJ Epstein, RP Erickson, A Wynshaw-Boris (Eds), Oxford University Press, New York (in press).

Patents

EH domain containing genes and proteins. USA Patent no. 6,552,177.

PCT/IL2005/000530 filed 24/05/2005 Title: Methods and kits for diagnosis and/or assessing severity and treatment of Gaucher disease.