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Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease
Marie-Pierre Audrézet1, Christine Corbiere2, Said Lebbah2
1Laboratory of Molecular Genetics and Histocompatibility, University Hospital of Brest, Institut National de la Santé et de la Recherche Médicale, U1078, Brest, France;
Insights
Genetic variations in polycystic kidney disease genes (PKD1, PKD2) are more common in early autosomal dominant polycystic kidney disease (ADPKD) patients. These additional genetic variations may influence disease severity.
Area of Science:
- Genetics
- Nephrology
- Pediatric Medicine
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) can present prenatally and recur in families, suggesting genetic modifiers.
- Previous reports indicate rare cases of ADPKD with additional genetic variations in PKD1, HNF1B, or PKHD1.
- Understanding these genetic factors is crucial for early ADPKD diagnosis and management.
Purpose of the Study:
- To determine the frequency of additional genetic variations in PKD1, PKD2, HNF1B, and PKHD1 in early-onset ADPKD.
- To compare the prevalence of these variations in early ADPKD versus adult-onset ADPKD.
- To investigate the potential role of these variations in disease severity.
Main Methods:
- Genetic screening of PKD1, PKD2, HNF1B, and PKHD1 in 42 patients with early ADPKD from 41 families.
- Analysis of familial mutations and inheritance patterns of additional variations.
- Comparison of variation frequencies with a cohort of 174 adult ADPKD patients.
Main Results:
- Additional genetic variations in PKD genes were found in 37.2% of early ADPKD patients, significantly higher than 14.4% in adult ADPKD patients (P=0.001).
- Two patients had de novo PKD1 mutations; most others had inherited variations.
- No HNF1B variations or PKHD1 biallelic mutations were identified in the early ADPKD cohort.
Conclusions:
- Additional genetic variations in PKD1 and PKD2 are more prevalent in early-onset ADPKD.
- The increased frequency suggests these variations may contribute to the early onset or severity of ADPKD.
- Disease severity in ADPKD may be inversely related to polycystin 1 function levels.
Abstract:
Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, and PKHD1 associated with the familial PKD mutation in early ADPKD, these four genes were screened in 42 patients with early ADPKD in 41 families. Two patients were associated with de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%, P=0.001) patients with adult ADPKD. No HNF1B variations or PKHD1 biallelic mutations were identified. These results suggest that, at least in some patients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.
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