Genetics; Hyperaldosteronism; Mutation; Nephrology; Lymphoma, T-Cell, Cutaneous
High Performance Computation
The common human diseases that account for the vast majority of morbidity and mortality in human populations are known to have underlying inherited components. Advances in human genetics have made the identification of genetic variants contributing to these traits feasible. Such identification promises to revolutionize the diagnostic and therapeutic approaches to these disorders. We have gone on from these starting points to use biochemistry and animal models to define the mechanisms linking genotype and phenotype. These findings have provided new insight into normal and disease biology, are identifying new pathways underlying disease pathogenesis, and are identifying new targets for development of novel therapeutics.
Specialized Terms: Molecular genetics of common human diseases
Extensive Research Description
By investigation of rare families recruited from around the world with extreme phenotypes suggesting genetic causation, we have identified genes that cause to these traits, putting a molecular face on their pathogenesis. In 2009 we reduced to practice the rapid and inexpensive sequencing of all genes in the genome and have used this platform for discovery of rare mutations with large effect in cardiovascular disease, cancer, kidney disease, skin disease and immunologic disease. These studies have revealed new pathways and mechanisms that regulate metabolic traits including blood pressure, bone mass, and electrolyte homeostasis, and genes that when mutated cause diverse diseases including heart attacks, strokes, kidney disease, cancer, autoinflammatory disease, skin disease and congenital heart disease. These studies have defined new strategies for disease gene discovery and point to the opportunity to determine the consequence of mutation of every gene in the human genome.
Genomic landscape of cutaneous T cell lymphoma.
Choi J , Goh G, Walradt T, Hong BS, Bjornson RD, Overton JD, Foss FM, Edelson RL, Schatz DG, Boggon TJ, Girardi M, Lifton RP. Genomic landscape of cutaneous T-cell lymphoma. Nat Genet, 2015 (in press).
Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.
Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014; 46:1135-9. PMCID: 4177367
Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.
Goh G, Scholl UI, Healy JM, Choi M, Prasad ML, Nelson-Williams C, Kunstman JW, Korah R, Suttorp AC, Dietrich D, Haase M, Willenberg HS, Stålberg P, Hellman P, Akerström G, Björklund P, Carling T, Lifton RP. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet. 2014; 46(6):613-7. PMCID: 4074779
De novo mutations in histone modifying genes in congenital heart disease.
Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton J, Romano-Adesman A, Bjornson R, Breitbart R, Brown K, Carriero N, Cheung Y, Deanfield J, DePalma S, Fakhro K, Glessner J, Hakonarson H, Italia M, Kaltman J, Kaski J, Kim R, Kline J, Lopez A, Mane S, Mitchell L, Newburger J, Pe'er I, Porter G, Sanders S, Seiden H, State M, Wang W, Warburton D, White P, Williams I, Zhao H, Seidman J, Brueckner M, Chung W, Gelb B, Goldmuntz E, Seidman C, Lifton RP. De novo mutations in histone modifying genes in congenital heart disease. Nature 498:220 – 223, 2013. PMID:23665959.
Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia.
Shibata S, Rinehart J, Zhang J, Moeckel G, Castañeda-Bueno M, Stiegler AL, Boggon TJ,Gamba G, Lifton RP. Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia. Cell Metabolism, Cell Metab. 2013, 18:660-71 (cover) PMID:24206662
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
Lemaire M, Fremeaux-Bacci V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Mobili F, Mafrtinez F, Ji W, Overton JD, Mane S, Nürnberg G, Altmüller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nürnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genetics 45:531-536, 2013. PMID 23542698
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Välimäki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 482:98-102. 2012. PMID: 22266938
K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.
Choi M, Scholl UI, Yue P, Bjorkland P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lois E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331:768-772, 2011.
Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.
Choate KA, Lu Y, ZhouJ, Choi M, Elias PM, Farhi A, Nelson-Williams C, Crumrine D, Williams ML, Nopper AJ, Bree A, Milstone LM, and Lifton RP. Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. Science 330:94-97, 2010.
Sites of regulated phosphorylation that control K-Cl cotransporter activity.
Rinehart, J., Maksimova, Y.D., Tanis, J.E., Stone, K.L., Hodson, C.A., Zhang, J.,Risinger, M., Pan, W., Wu, D., Colangelo, C.M., Forbush B, Joiner CH, Gulcicek E.E., Gallagher P.G., Lifton, R.P. Sites of regulated phosphorylation that control K-Cl cotransporter activity. Cell, 138, 525-536, 2009.