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Richard Spritz, M.D. SOM Program Director

Mapping, discovery, and function of disease genes affecting skin and craniofacial development and autoimmunity


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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 40 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 melanocytes, and a series of disorders of organelle biogenesis in which pigment-forming melanosomes ore incorrectly assembled.

For over two decades, my lab has focused on the most common pigmentation disorder, vitiligo, a complex polygenic autoimmune disease in which melanocytes are destroyed by the immune system, giving rise to patches of white skin and hair. Vitiligo is epidemiologically associated with several other autoimmune diseases, autoimmune thyroid disease, type 1 diabetes, rheumatoid arthritis, and others, suggesting that these different autoimmune diseases share common underlying susceptibility genes. By various approaches, including candidate gene association studies, genomewide linkage, and genomewide association studies, we have identified 52 different genetic loci involved with vitiligo susceptibility, some of which are also implicated in other autoimmune diseases. We have identified most of the corresponding genes and in many cases specific causal gene variants. The corresponding proteins comprise melanocyte antigens, immunoregulators, and apoptotic regulators, defining a complex circuit of melanocyte-specific autoimmune triggering, targeting, and destruction. We are currently using these loci to dissect the genetic epidemiology and genetic architecture of vitiligo in a large cohort of vitiligo cases and extended families.

My lab has also carried out extensive studies of one of the most common of all major birth defects, cleft lip and palate, as well as the genetic basis of variation of normal human facial shape. We are currently assembling a “library” of 3D facial scans of many thousands of patients with various facial dysmorphic syndromes, with the goal of developing a prototype system for automated syndrome diagnosis from 3D facial images.

Selected Publications

Jin Y, Roberts GHL, Ferrara TM, Ben S, van Geel N, Wolkerstorfer A, Ezzedine K, Siebert J, Neff P, Palmer BE, Santorico SA, Spritz RA (2019). Early-onset autoimmune vitiligo associated with an enhancer variant haplotype that upregulates class II HLA expression. Nat Comms, in press.

Jin Y, Birlea SA, Fain PR, Ferrara TM, Ben S, Andersen G, Burgess K, Holland PJ, Siebert J, Hartmann A, Lienert A, Luiten RM, Wolkerstorfer A, van der Veen JPW, van Geel N, Lambert J,  Bennett DC, Taïeb A, Ezzedine K, Kemp EH, Gawkrodger DJ, Weetman AP, Koks S, Prans E, Kingo K, Karelson M, Wallace MR, McCormack WT, Overbeck A, Moretti S, Colucci R, Picardo M, Silverg NB, Olssen M, Valle Y, Korobko I, Böhm M, Lim H, Hamzavi I, Zhou L, Mi Q-S, Santorico S, Spritz RA (2016). Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet 48:1418-1424. doi: 10.1038/ng.3680. PMID: 27723757. PubMed Central PMCID: PMC5120758

Hayashi M, Jin Y Yorgov D, Santorico SA, Hagman J, Ferrara TM, Jones KL, Cavalli G, Dinarello CA, Spritz RA. Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo. Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1357-62. doi: 10.1073/pnas.1525001113. Epub 2016 Jan 19. PubMed PMID: 26787886. PubMed Central PMCID: PMC4747738.

Cavalli G, Hayashi M, Jin Y, Yorgov D, Santorico SA, Holcomb C, Rastrou M, Erlich H, Tengesdal IW, Dagna L, Neff CP, Palmer BE, Spritz RA, Dinarello CA. (2016). MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo. Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1363-8. doi: 10.1073/pnas.1523482113. Epub 2016 Jan 19. PubMed PMID: 26787888. PubMed Central PMCID: PMC4747741.

Cole JB, Manyama M, Kimwaga E, Mathayo J, Larson JR, Liberton DK, Lukowiak K, Ferrara TM, Riccardi SL, Li M, Mio W, Prochazkova M, Williams T, Li H, Jones KL, Klein OD, Santorico SA, Hallgrimsson B, Spritz RA. (2016). Genomewide association study of African children identifies association of SCHIP1 and PDE8A with facial size. PLoS Genet. 2016 Aug 25;12(8):e1006174. PMID: 27560698.

Shaffer JR, Orlova E, Lee MK, Leslie EJ, Raffensperger ZD, Heike CL, Cunningham ML, Hecht JT, Kau CH, Nidey NL, Moreno LM, Wehby GL, Murray JC, Laurie CA, Laurie CC, Cole J, Ferrara T, Santorico S, Klein O, Mio W, Feingold E, Hallgrimsson B, Spritz RA, Marazita ML, Weinberg SM. (2016). Genome-wide association study reveals multiple loci influencing normal human facial morphology. PLoS Genet. 2016 Aug 25;12(8):e1006149. PMID: 27560520.

Levandowski CB, Mailloux CM, Ferrara TM, Gowan K, Ben S, Jin Y, McFann KK, Holland PJ, Fain PR, Dinarello CA, Spritz RA. NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1β processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2952-6. PubMed PMID: 23382179; PubMed Central PMCID: PMC3581876.

Jin Y, Birlea SA, Fain PR, Ferrara TM, Ben S, Riccardi SL, Cole JB, Gowan K, Holland PJ, Bennett DC, Luiten RM, Wolkerstorfer A, van der Veen JP, Hartmann A, Eichner S, Schuler G, van Geel N, Lambert J, Kemp EH, Gawkrodger DJ, Weetman AP, Taïeb A, Jouary T, Ezzedine K, Wallace MR, McCormack WT, Picardo M, Leone G, Overbeck A, Silverberg NB, Spritz RA. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat Genet. 2012 May 6;44(6):676-80. PubMed PMID: 22561518; PubMed Central PMCID: PMC3366044.

Jin Y, Birlea SA, Fain PR, Gowan K, Riccardi SL, Holland PJ, Mailloux CM, Sufit AJ, Hutton SM, Amadi-Myers A, Bennett DC, Wallace MR, McCormack WT, Kemp EH, Gawkrodger DJ, Weetman AP, Picardo M, Leone G, Taïeb A, Jouary T, Ezzedine K, van Geel N, Lambert J, Overbeck A, Spritz RA. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med. 2010 May 6;362(18):1686-97. PubMed PMID: 20410501; PubMed Central PMCID: PMC2891985.

Jin Y, Birlea SA, Fain PR, Mailloux CM, Riccardi SL, Gowan K, Holland PJ, Bennett DC, Wallace MR, McCormack WT, Kemp EH, Gawkrodger DJ, Weetman AP, Picardo M, Leone G, Taïeb A, Jouary T, Ezzedine K, van Geel N, Lambert J, Overbeck A, Spritz RA. Common variants in FOXP1 are associated with generalized vitiligo. Nat Genet. 2010 Jul;42(7):576-8. PubMed PMID: 20526340; PubMed Central PMCID: PMC2893242.

Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007 Mar 22;356(12):1216-25. PubMed PMID: 17377159.

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.

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.

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.

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.

Sözen MA, Suzuki K, Tolarova MM, Bustos T, Fernández Iglesias JE, Spritz RA. Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela. Nat Genet. 2001 Oct;29(2):141-2. PMID: 11559849.

Suzuki K, Hu D, Bustos T, Zlotogora J, Richieri-Costa A, Helms JA, Spritz RA. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet. 2000 Aug;25(4):427-30. PubMed PMID: 9758630.

Oh J, Bailin T, Fukai K, Feng GH, Ho L, Mao JI, Frenk E, Tamura N, Spritz RA. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet. 1996 Nov;14(3):300-6. PubMed PMID: 8896559.

Nagle, D.L., Karim, M.A., Woolf, E.A., Holmgren, L., Bork, P., Misumi, D.J., McGrail, S.H., Dussault, B.J., Jr., Perou, C.M., Boissy, R.E., Duyk, G.M., Spritz, R.A., and Moore, K.J. (1996). Mutations in the human orthologue of the mouse beige gene in patients with Chediak-Higashi syndrome. Nat. Genet. 14:307-311.

Fukai, K., Holmes, S.A., Lucchese, N.J., Siu, V.M., Weleber, R.G., Schnur, R.E., and Spritz, R.A. (1995). Autosomal recessive ocular albinism associated with a functionally significant tyrosinase gene polymorphism. Nat. Genet. 9:92-95.

Lee, S.-T., Nicholls, R.D., Bundey, S., Laxova, R., Musarella, M., and Spritz, R.A.  (1994).  Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albin¬ism. New England J. Med. 330:529-534.

Rinchik EM, Bultman SJ, Horsthemke B, Lee ST, Strunk KM, Spritz RA, Avidano KM, Jong MT, Nicholls RD. A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Nature. 1993 Jan 7;361(6407):72-6. PubMed PMID: 8421497.

Giebel LB, Spritz RA. Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8696-9. PubMed PMID: 1717985; PubMed Central PMCID: PMC52576.

Giebel, L.B., Strunk, K.M., King, R.A.,  Hanifin, J.M., and Spritz, R.A.  (1990).  A frequent tyrosinase gene mutation in classic, tyrosinase-negative (type IA) oculocutaneous  albinism.  Proc. Natl. Acad. Sci. U.S.A. 873255-3258.

Spritz RA, Strunk KM, Giebel LB, King RA. Detection of mutations in the tyrosinase gene in a patient with type IA oculocutaneous albinism. N Engl J Med. 1990 Jun 14;322(24):1724-8. PubMed PMID: 2342539.

van Santen, V.L. and  Spritz, R.A. (1987).  Nucleotide sequence of a bean (Phaseolus vulgaris) U1 snRNA gene:  Implications for plant pre-mRNA splicing.  Proc. Natl. Acad. Sci. U.S.A. 84:9094-9098.

Giebel, L.B., van Santen, V.L., Slightom, J.L., and  Spritz, R.A. (1985).  Nucleotide sequence, evolution, and expression of the fetal globin gene of the spider monkey Ateles geoffroyi.  Proc. Natl. Acad. Sci. U.S.A. 82:6985-6989.

van Santen, V.L. and Spritz, R.A.  (1985).  mRNA precursor splicing in vivo: Sequence requirements determined by  deletion analysis of an intervening sequence.  Proc. Natl. Acad. Sci. U.S.A.  82:2885-2889.

Lang KM, Spritz RA. RNA splice site selection: Evidence for a 5'3' scanning model.  Science. 1983 Jun 24;220(4604):1351-5. PubMed PMID: 6304877.

Spritz RA, Jagadeeswaran P, Choudary PV, Biro PA, Elder JT, deRiel JK, Manley JL, Gefter ML, Forget BG, Weissman SM. Base substitution in an intervening sequence of a beta+-thalassemic human globin gene. Proc Natl Acad Sci USA. 1981 Apr;78(4):2455-9. PubMed PMID: 6264477; PubMed Central PMCID: PMC319365.

Efstratiadis A, Posakony JW, Maniatis T, Lawn RM, O'Connell C, Spritz RA, DeRiel JK, Forget BG, Weissman SM, Slightom JL, Blechl AE, Smithies O, Baralle FE, Shoulders CC, Proudfoot NJ. The structure and evolution of the human beta-globin gene family. Cell. 1980 Oct;21(3):653-68. PubMed PMID: 6985477.

Spritz RA, DeRiel JK, Forget BG, Weissman SM. Complete nucleotide sequence of the human delta-globin gene. Cell. 1980 Oct;21(3):639-46. PubMed PMID: 7438204.

Spritz, R.A., Soifer, S.J., Siegel, N.J.,  and Mahoney, M.J. (1978).  False-negative A.F.P. screen for congenital nephrosis Finnish type.  Lancet ii:1251.