Stefan Somlo, M.D.

C.N.H. Long Professor of Medicine and Genetics.
Chief of Nephrology.

A.B., 1980: Harvard College
M.D., 1984: College of Physicians and Surgeons, Columbia University
Residency: Albert Einstein College of Medicine
Fellowship: Yale University

E-mail: stefan.somlo@yale.edu

We have used our positional cloning-based discovery of three genes mutated in human polycystic kidney and liver diseases as entry points to understanding the pathways essential in the development and maintenance of lumen forming epithelia. This has led to the discovery that primary apical cilia serve essential sensory functions in polarized epithelia. The polycystin-related pathways serve to maintain the highly structured luminal arrangement by acting as flow sensors or as lumen diameter sensors. At least one of the polycystic disease proteins, polycystin-2, functions in other sensory cilia as well—most notably embryonic nodal cilia that have a central role in left-right axis determination. We are studying a series of engineered mouse models with conditional tissue-specific and inducible Cre/lox-mediated inactivation of Pkd1, Pkd2, Prkcsh (Pld1) and Pkhd1 to define the actions of the polycystin-related pathways in vivo. We are using epithelial cell lines lacking these proteins to define the intracellular pathways regulated by the polycystin-dependent ciliary signals. The initial step of polycystin-2 signaling is an increase in cytosolic Ca2+, but the mechanisms responsible for activation of the resultant cellular proliferation and cytoskeletal rearrangements are the subject of our current studies. In parallel with these efforts, we continue to pursue positional cloning of additional related human disease genes, most notably a second gene for polycystic liver disease.

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References

Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S. (2002) Polycystin-2 is an intracellular calcium release channel. Nature Cell Biol 4:191-197.

Onuchic L, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, Bergmann C, Senderek J, Esquivel E, Zeltner R, Rudnick-Schoneborn S, Mrug M, Sweeney W, Avner E, Zerres K, Guay-Woodford L, Somlo S, Germino G. (2002) PKHD1, the polycystic kidney and hepatic disease 1 gene encodes a novel large protein containing multiple IPT domains and PbH1 repeats. Am J Hum Genet. 70:1305-1317.

Wu G, Tian X, Nishimura S, Markowitz GS, D’Agati Y, Hoon-Park J, Yao L, Li L, Geng L, Zhaou H, Edelmann W, Somlo S. (2002) Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Hum Mol Genet, 11:1845-1854.

Qian Q, Li A, King BF, Kamath PS, Lager DJ, Huston J 3rd, Shub C, Davila S, Somlo S, Torres VE. (2003) Clinical profile of autosomal dominant polycystic liver disease. Hepatology, 37:164-171.

Li A, Davila S, Furu L, Qian Q, Tian X, Kamath PS, King BF Torres VE, and Somlo S. (2003) Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am J Hum Genet, 72:691-703.

Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LSB, Somlo S, and Igarashi P. (2003) Kidney-specific inactivation of KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci U.S.A., 100:5286-91.

McGrath J, Somlo S, Makova S, Tian X, and Brueckner M. (2003) Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell, 114:61-73.

Furu L, Onuchic LF, Gharavi A, Hou X, Esquivel EL, Nagasawa Y, Bergmann C, Senderek J, Avner E, Zerres KZ, Germino GG, Guay-Woodford LM, and Somlo S. (2003) Milder presentation of recessive polycystic kidney disease requires presence of amino acid substitution mutations. J Am Soc Nephrol, 14:2004-14.