Richard Spritz, M.D.
Program Director
Mapping, discovery, and function of disease genes affecting skin and
craniofacial development and autoimmunity
My laboratory studies the molecular basis of human genetic
diseases, including mapping, discovery, and mutational and functional
analysis of human disease genes. Over the past 20 years we have characterized
a number of single-gene genetic disorders of pigmentation such as albinism
(OCA), in which little or no melanin pigment is made due to functional
defects of melanocytes, piebaldism, a defect of development in which neural
crest-derived are not targeted correctly to the skin, and a series of
related disorders of organelle biogenesis. This last, in particular, remains
the subject of considerable current work in my laboratory, and we recently
identified the genes for a number of new disorders of organelle biogenesis,
Hermansky-Pudlak syndrome types 3, 4, 5, 6, and 7, which turn out to be
homologous to specific mouse mutants that exhibit similar phenotypes and
thus provide ready-made animal models for studies of disease pathogenesis
and treatment.
We also direct an international collaborative project to map and identify
genes involved in vitiligo, a common polygenic, multifactorial autoimmune
disorder in which acquired patchy depigmentation results from loss of
melanocytes on an autoimmune basis, as well as other types of autoimmune
disease, including Addison disease, hypothyroidism, and type 1 diabetes.
We have mapped a series of autoimmunity susceptibility genes, to chromosomes
1, 7, 8, 9, and 17, which appear to predispose to autoimmunity in general,
particularly vitiligo, thyroid disease, and perhaps also diabetes, Addison
disease, and lupus. We are currently in the process of more precisely
localizing these genes and trying to identify them and to analyze their
roles in causing specific autoimmune diseases.
Finally, we are also studying one of the most common of all major birth
defects, cleft lip and palate. We previously identified PVRL1 as the gene
responsible for a rare cleft lip/palate syndrome, CLPED1. and showed that
PVRL1 is also involved in the most common, 'non-syndromic' form of cleft
lip/palate, in both South American and North American populations. We
are now attempting to map and identify genes that predispose to non-syndromic
cleft lip in northwestern Kenya, where there is frequent occurrence of
an unusual form of cleft lip in specific tribal groups, possibly signaling
the existence of unique predisposing genetic factors in this population.
Recent Publications
Spritz, R.A. (1999). Chediak-Higashi syndrome. In, Primary Immunodeficiency Diseases, Ochs H.D., Smith, C.I.E., Puck, J.M., eds. (Oxford, New York), pp. 389-396.
Spritz, R.A., Oh, J. (1999). HPS gene mutations in Hermansky-Pudlak syndrome. Am. J. Hum. Genet. 64:658-659.
Spritz, R.A. (1999). Multi-organellar disorders of pigmentation—tied up in traffic. Clin. Genet. 55:309-317.
Spritz, R.A. (1999). Multi-organellar disorders of pigmentation—intracellular traffic jams in mammals, flies, and yeast. Trends in Genetics 15:337-340.
Spritz, R.A. (2000). Hermansky-Pudlak syndrome and pale ear: Melanosome-making for the millennium. Pigment Cell Res. 13:15-20.
Oh, J., Liu, Z.-X., Feng, G.H., Raposo, G., Spritz, R.A. (2000). The Hermansky-Pudlak Syndrome (HPS) protein is part of a high-molecular weight complex involved in biogenesis of early melanosomes. Hum. Mol. Genet. 9:375-385.
Suzuki, K., Hu, D., Bustos, T., Zlotogora, J., Richieri-Costa, A., Helms, J.A., Spritz, R.A. (2000). Mutations of PVRL1 cell-cell adhesion molecule/Herpesvirus receptor gene in cleft lip/palate-ectodermal dysplasia. Nature Genet. 25:427-30.
Spritz, R.A. (2001). Albinism. In, Encyclopedia of Genetics, Brenner, S., Miller, J., eds. (Academic Press, New York), pp. 25-27.
Toyofuku, K., Wada, I., Spritz, R.A., and Hearing, V.J. (2001). The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem. J. 355:259-269.
Oh, J., LeCras, T., Spritz, R.A. (2001). Characterization and evolutionary comparison of rat Hps cDNA and exclusion of red-eyed dilution (r) locus. Mammalian Genome 12:466-468.
Akahoshi, K., Fukai, K., Kato, A., Kimiya, S., Kubota, T., and Spritz, R. A. (2001). Duplication of 15q11.2-q14, including the P gene, in a patient with generalized skin hyperpigmentation. Am. J. Med. Genet. 104:299-302.
Spritz, R.A. (2001). The genetics and epigenetics of orofacial clefts. Current Opinion Pediatrics 13:556-560.
Sozen, M., Suzuki, K., Tolarova, M.M., Bustos, T., Iglesias, J.E.F., Spritz, R.A. (2001). Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nature Genet. 29:141-142.
Suzuki, T., Li, W., Zhang, Q., Novak, E.K., Sviderskaya, E.V., Wilson, A., Bennett, D.C., Roe, B.A., Swank, R.T., Spritz, R.A. (2001). The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky-Pudlak syndrome-3 gene. Genomics 78:30-37.
Karim, M.A., Suzuki, K., Fukai, K., Oh, J., Nagle, D.L., Moore, K.J., Barbosa, E., Falik-Borenstein, T., Filipovich, A., Ishida, Y., Kivrikko, S., Klein, C., Kreuz, F., Levin, A., Miyajima, H., Russo, C., Uyama, E., Vierimaa, O., Spritz, R.A. (2002). Chediak-Higashi syndrome gene (CHS1) organization and mutations in the childhood and “adult” forms of the disorder. Am. J. Med. Genet. 108:16-22.
Spritz, R.A. (2002). Biology and disorders of melanosome biogenesis: The Hermansky-Pudlak and Chediak-Higashi syndromes. In, UV-Induced Melanogenesis. Ortonne, J.-P., ed. Martin Dunitz, Ltd., London, in press.
Alkhateeb, A., Stetler, G.L., Old, W., Talbert, J., Uhlhorn, C., Taylor, M., Fox, A., Miller, C., Dills, D.G., Ridgway, E.C., Bennett, D.C., Fain, P.R., and Spritz, R.A. (2002). Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2 Hum. Mol. Genet. 11:661-667.
Suzuki, T., Li, W., Zhang, Q., Karim, A., Novak, E.K., Sviderskaya, E.V., Hill, S.P., Bennett, D.C., Levin, A.V., Nieuwenhuis, H.K. Fong, C.-T., Castellan, C., Miterski, B., Swank, R.T., and Spritz, R.A. (2002). Hermansky-Pudlak Syndrome due to mutations in the human homologue of the mouse light ear (le) gene (HPS4). Nature Genet. 30:321-324.
Suzuki, T., Oiso, N., Gautam, R., Novak, E.K., Panthier, J.-J., Suprabha, P.G., Vida, T., Swank, R.T., and Spritz, R.A. (2003). The mouse organellar biogenesis mutant buff (bf) results from a mutation in Vps33a, a homologue of yeast vps33 and Drosophila carnation (car). Proc. Natl. Acad. Sci. U.S.A. 100:1146-1150.
Zhang, Q., Zhao, B., Li, W., Oiso, N., Novak, E.K., Rusiniak, M.E., Gautam, R., Chintala, S., O’Brien, E.P., Zhang, Y., Roe, B.A., Elliott, R.W., Eicher, E.M., Liang, P., Kratz, C., Legius, E., Spritz, R.A., O’Sullivan, T.N. , Copeland, N.G., Jenkins, N.A. and Swank, R.T. (2003). Ruby-eye-2 and ruby-eye encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nature Genet. 33:145-153.
Spritz, R.A., Chiang., P.-W., Oiso, N., and Alkhateeb, A. (2003). Human and mouse disorders of pigmentation. Curr. Opinion Genetics Dvlpt. 13:284-289.
Alkhateeb, A., Fain, P.R., Thody, A., Bennett, D.C., and Spritz, R.A. (2003). Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 16:208-214.
Spritz, R.A. (2003). Chediak-Higashi syndrome. In, Primary Immunodeficiency Diseases, 2nd ed. Ochs H.D., Smith, C.I.E., Puck, J.M., eds. (Oxford, New York), in press.
Fain, P.R., Gowan, K., LaBerge, G.S., Alkhateeb, A., Stetler, G.L., Talbert, J., Bennett, D.C., and Spritz, R.A. (2003) A genomewide screen for autoimmune vitiligo: Confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. Am. J. Hum. Genet. 72:1560-1564.
Chiang, P.-W., Oiso, N., Gautam, R., Swank, R.T., and Spritz, R.A. (2003) The HPS1 and HPS4 proteins are components of two complexes, BLOC-3 and BLOC-4, involved in biogenesis of lysosome-related organelles. J. Biol Chem. 278:20332-20337.
Sánchez-Martín, M., Pérez-Losada, J., Rodríguez-García, A., González-Sánchz, B., Korf, B.R., Kuster, W., Moss, C., Spritz, R.A., and Sánchez-García, I. (2003). Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am. J. Med. Genet. 122A:125-132.
Li, W., Zhang, Q., Oiso, N., Novak, E.K., Gautam, R., O’Brien, E.P., Tinsley, C.L., Blake, D.J., Spritz, R.A., Copeland, N.G., Jenkins, N.A., Amato, D., Roe, B.A., Starcevic, M., Dell’Angelica, E.C., Elliott, R.W., Mishra, V., Kingsmore, S.F., Paylor, R.E., and Swank, R.T. (2003). Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutations in dysbindin, a dystrobrevin-interacting protein and a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nature Genet. 35:84-89.
Spritz, R.A., Itin, P.H., and Gutmann, D.H. (2004). Piebaldism and neurofibromatosis type 1: Horses of very different colors. J. Investig. Dermatol. 122:xxxiv-xxxv.
Spritz, R.A., Gowan, K., Bennett, D.C., and Fain, P.R. (2004). Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am. J. Hum. Genet. 74:188-191.
Akahoshi, K., Spritz, R.A., Fukai, K., Mitsui, N., Matsushima, K., and Ohashi, H.(2004). Mosaic supernumerary inv dup(15) chromosome with four copies of the P gene in a boy with pigmentary dysplasia. Am. J. Med. Genet. 126A:290-292.
Oiso, N., Riddle, S.R., Serikawa, T., Kuramoto, T., Spritz, R.A. (2004). The rat Ruby (R) locus is Rab38: Identical mutations in Fawn-Hooded and Tester-Moriyama rats derived from an ancestral Long Evans rat rub-strain. Mammalian Genome 15:307-314.
Spritz, R.A. (2005). Genetic hypomelanosis: Disorders characterized by congenital depigmentation. In, Nordlund, J.J., Boissy, R.E., Hearing, V.J., King, R.A., Oetting, W.S., and Ortonne, J.-P., eds. The Pigmentary System: Physiology and Pathophysiology. 2nd Ed. Blackwell, Oxford, in press.
Spritz, R.A. (2005). Melanocyte development. In, Nordlund, J.J., Boissy,
R.E., Hearing, V.J., King, R.A., Oetting, W.S., and Ortonne, J.-P., eds.
The Pigmentary System: Physiology and Pathophysiology. 2nd Ed.
