Human Molecular Genetics, 2002, Vol. 11, No. 16 1845-1854
© 2002 Oxford University Press
Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease
1Department of Internal Medicine, 2Department of Epidemiology and Public Health and 3Department of Genetics, Yale University School of Medicine, New Haven, CT, USA, 4Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA and 5Department of Medicine and 6Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
Received March 19, 2002; Accepted June 8, 2002
Autosomal dominant polycystic kidney disease (ADPKD) occurs by germline mutation in PKD1 or PKD2. Evidence of homozygous inactivation of either gene in human cyst lining cells as well as in mouse knockout models strongly supports a two-hit mechanism for cyst formation. Discovery of trans-heterozygous mutations in PKD1 and PKD2 in a minority of human renal cysts has led to the proposal that such mutations also can play a role in cyst formation. In the current study, we investigated the role of trans-heterozygous mutations in mouse models of polycystic kidney disease. In Pkd1+/-, Pkd2 +/- and Pkd1+/- : Pkd2 +/- mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year. In keeping with the two-hit mechanism of cyst formation, approximately 70% of kidney cysts in Pkd2 +/- mice exhibited uniform loss of polycystin-2 expression. Cystic disease in trans-heterozygous Pkd1+/- : Pkd2 +/- mice, however, was notable for severity in excess of that predicted by a simple additive effect based on cyst formation in singly heterozygous mice. The data suggest a modifier role for the ‘trans’ polycystin gene in cystic kidney disease, and support a contribution from threshold effects to cyst formation and growth.
* To whom correspondence should be addressed at: Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06519-1418, USA. Tel: +1 203 737 2974; Fax: +1 203 737 5313; Email: stefan.somlo{at}yale.edu
Correspondence may also be addressed to Guanqing Wu, Department of Medicine, Vanderbilt University, 2215 Garland Avenue, Nashville, TN 37232-0275, USA. Tel: +1 6159361761, Fax: +1 6159362661, Email: guanqing.wu@vanderbilt.edu.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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