Richard P. Lifton

Professor of Genetics and Medicine; Chairman of Genetics; Investigator, Howard Hughes Medical Institute

Research Interests:

Genetic and Molecular Determinants of Cardiovascular and Kidney Disease

Honors:

Smith-Kline Beecham Outstanding Young Investigator Award
Abbott Award, American Society of Hypertension

The common human diseases that account for the vast majority of morbidity and mortality in our society are known to have underlying inherited components. Rapid advances in molecular genetics have led to a stage where identification of genetic variants contributing to these common but complex traits is feasible. Such identification promises to revolutionize the diagnostic and therapeutic approaches to these disorders.

Current Research

Hypertension affects over 50 million Americans, contributing to over 200,000 deaths annually from myocardial infarction, stroke and end-stage renal disese (ESRD). We are using genetic approaches to identify the elusive primary determinants of hypertension and of these specific clinical end-points.

Our studies have led to identification of four genetic variants affecting blood pressure in humans. One of these mutations is a chimeric gene duplication arising from unequal crossing over that leads to ectopic production of the key hormone determining salt and water homeostasis. The result is a severe form of hypertension characterized by a high incidence of early death from cerebral hemorrhage. We have developed a simple genetic test for this disorder that is in clinical use. The second variant is in angiotensinogen and results in increased activity of the renin-angiotensin system. This causes modest effects on blood pressure in millions of individuals. Finally, mutations in two different subunits of the renal sodium channel, which regulates net renal sodium reabsorption, also cause a severe form of hypertension (see figure). The mutations delete the normal cytoplasmic carboxy termini from the sodium channel subunits, resulting in constitutive activation of channel activity leading to hypertension. Continuing studies of families segregating for these mutations permits assessment of the quantitative effects on blood pressure, and reveals broad phenotypic variation in subjects inheriting the same mutation by descent from a common ancestor. Subjects with low or high pressure cluster in specific branches of the families, suggesting the presence of modifiers in the population. Identification of these genetic modifiers may be broadly relevant to blood pressure regulation.

Recent studies have demonstrated familial clustering of two of the major clinical consequences of hypertension- intracranial aneurysm causing cerebral hemorrhage and ESRD. The study of families with these extreme end-points may identify genes that predispose hypertensives to these clinical outcomes, and may provide novel insights into disease pathogenesis. We have recently used linkage analysis to map a gene causing cavernous malformation of the vascular system of the brain to a segment of chromosome 7q.

These studies have demonstrated the utility of genetic approaches to complex traits, and provide optimism that this approach will permit dissection of the key determinants of common disease.

Mutations that truncate the cytoplasmic carboxy terminus of either the beta subunit of the renal epithelial sodium channel (beta-ENaC) or the gamma subunit (gamma-ENaC) result in constitutive activation of channel activity, leading to increased sodium reabsorption, plasma volume expansion and hypertension. These mutations result in the autosomal dominant hypertensive disease known as Liddle's syndrome.

Representative Publications:

Shimkets, R.A., Warnock, D.G., Bositis, C., Nelson-Williams, C., Hansson, J.H., Schambelan, M., Gill, J.R., Ulick, S., Milora, R.V., Findling, J.W., Canessa, C.M., Rossier, B.C., Lifton, R.P. Liddle's syndrome: Heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 79:407-414, 1994.

Lifton RP. Molecular Genetics of Human Blood Pressure Variation. Science, 272:676-680, 1996.

Karet FE, Finberg KE, Nelson RD, Nayir A, Mocan H, Sanjad SA, Rodriguez-Soriano J, Santos F, Cremers C, Di Pietro A, Hoffbrand BI, Winiarski J, Bakkaloglu A, Ozen S, Dusunsel R, Goodyer P, Hulton SA, Wu DK, Skvorak A, Morton CC, Cunningham MJ, Jha V, and Lifton RP. Mutations in the B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nature Genetics 21:84-90, 1999.

Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ reabsorption. Science, 285:103-106, 1999.

Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai TF, Sigler P, Lifton RP. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science, 289:119-123, 2000.

Gharavi G, Yan Y, Scolari F, Schena P, Frasca GM, Giggheri GM, Cooper K, Amoroso A, Viola BF, Battini G, Caridi G, Canova C, Farhi A, Subramanian V, Woodford S, Julian B, Wyatt R, Lifton RP. Identification of a locus for IgA nephropathy, the most common cause of glomerulonephritis. Nature Genetics 2000 (in press).

Updated 28 August 2000