PKD1 – Polycystic Kidney Disease 1

PKD1 encodes polycystin-1, a large transmembrane protein whose mutations underlie autosomal dominant polycystic kidney disease type 1 (PKD1 – polycystic kidney disease 1). Genetic linkage and mutation analyses have firmly established PKD1 as causative, enabling presymptomatic diagnosis and family counselling.

Autosomal dominant inheritance is supported by linkage in 14 microsatellite marker families (SM7, SM6, CW3, CW2; SM7 especially informative) and by segregation in 41 Spanish families (PMID:1683919; PMID:7909986). Comprehensive screening of 67 Italian patients identified a novel nonsense mutation c.12061C>T (p.Arg4021Ter) segregating with disease and additional downstream missense changes (PMID:8911610).

Broader mutation surveys in 41 Bulgarian and Australian kindreds revealed seven disease-causing alterations—five truncating (e.g. c.11587delG), one splice (IVS37-10C>A), and one in-frame indel—accounting for 17% of that cohort (PMID:10923038). Over 149 unrelated probands have now been reported with diverse variant classes including nonsense, frameshift, splice, and missense alleles.

Functional assessments support a two-hit mechanism: analysis of cystic tissues with truncating PKD1 mutations showed retained polycystin-1 in ~80% of adult cysts but absent in early-onset and TSC2/PKD1 deletions (PMID:10504485). Promoter studies demonstrate PKD1 activation by β-catenin via TCF binding elements (PMID:12048202).

Mechanistic insights include impaired desmosomal junction formation in ADPKD epithelia lacking functional PC-1 (PMID:16187067) and dosage-dependent cystogenesis in a Pkd1 p.R3277C hypomorphic mouse model, recapitulating in utero-onset versus typical disease severity (PMID:23064367).

Integration of genetic and experimental data confirms haploinsufficiency of PKD1 as the primary disease mechanism. Ongoing large-scale sequencing and functional assays continue to refine variant interpretation. Key Take-home: Genetic testing of PKD1 ensures accurate diagnosis, guides family planning, and informs therapeutic development.

References

• Lancet (London, England) • 1991 • Rapid genetic analysis of families with polycystic kidney disease 1 by means of a microsatellite marker. PMID:1683919
• American Journal of Human Genetics • 1994 • Evidence of linkage disequilibrium in the Spanish polycystic kidney disease I population. PMID:7909986
• American Journal of Medical Genetics • 1996 • Autosomal dominant polycystic kidney disease (ADPKD) in an Italian family carrying a novel nonsense mutation and two missense changes in exons 44 and 45 of the PKD1 Gene. PMID:8911610
• Kidney International • 1999 • Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue. PMID:10504485
• Human Mutation • 2000 • Screening the 3' region of the polycystic kidney disease 1 (PKD1) gene in 41 Bulgarian and Australian kindreds reveals a prevalence of protein truncating mutations. PMID:10923038
• The Journal of Biological Chemistry • 2002 • The polycystic kidney disease-1 promoter is a target of the beta-catenin/T-cell factor pathway. PMID:12048202
• Histochemistry and Cell Biology • 2005 • Impaired formation of desmosomal junctions in ADPKD epithelia. PMID:16187067
• The Journal of Clinical Investigation • 2012 • Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. PMID:23064367

Evidence Based Scoring (AI generated)