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Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease
Guanqing Wu1, Xin Tian, Sayoko Nishimura
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA. guanquing.wu@vanderbilt.edu
Abstract:
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.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) cyst formation involves a two-hit gene inactivation mechanism. Trans-heterozygous mutations in PKD1 and PKD2 genes modify disease severity in mouse models, suggesting a role in cyst growth.
Area of Science:
- Genetics
- Nephrology
- Molecular Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation.
- The established two-hit hypothesis suggests homozygous inactivation of PKD1 or PKD2 causes cyst development.
- Trans-heterozygous mutations in PKD1 and PKD2 have been proposed to contribute to cystogenesis.
Purpose of the Study:
- To investigate the role of trans-heterozygous mutations in PKD1 and PKD2 in polycystic kidney disease pathogenesis using mouse models.
- To evaluate the impact of combined heterozygous mutations on cyst formation and disease severity.
Main Methods:
- Generation and analysis of Pkd1(+/-), Pkd2 (+/-), and Pkd1(+/-) : Pkd2 (+/-) mouse models.
- Assessment of renal cystic lesions, cyst formation, and survival rates.
- Evaluation of polycystin-2 expression in kidney cysts.
Main Results:
- Mild and variable renal cystic lesions were observed in singly heterozygous mice (Pkd1(+/-), Pkd2 (+/-)) with no impact on survival.
- Approximately 70% of kidney cysts in Pkd2 (+/-) mice showed a complete loss of polycystin-2 expression, supporting the two-hit model.
- Trans-heterozygous Pkd1(+/-) : Pkd2 (+/-) mice exhibited more severe cystic disease than predicted by an additive model, indicating a modifier effect.
Conclusions:
- The 'trans' polycystin gene acts as a modifier in polycystic kidney disease.
- Threshold effects likely contribute to the complex mechanisms of cyst formation and growth in ADPKD.
- These findings refine the understanding of genetic contributions to ADPKD pathogenesis.