PKD2 – Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary renal disorder characterized by progressive development of bilateral renal cysts and ultimately end-stage renal disease (ESRD). Mutations in PKD2 (HGNC:9009) account for approximately 10–15% of ADPKD cases, with a generally milder course and later onset of ESRD (mean age 70 years) compared with PKD1-related disease (mean age 56 years) (PMID:9773786).

Genetic analyses in eight Canadian kindreds identified PKD2 mutations in 8 of 11 families, yielding truncating alleles scattered between exons 1 and 11 and no clear genotype–severity correlation (PMID:9773786). In a cohort of 46 elderly ADPKD patients (age ≥63 years), 18 (39.1%) harbored PKD2 mutations, compared with 4 of 40 younger controls, confirming enrichment of PKD2 among late‐onset ESRD patients (PMID:11007674). These findings support autosomal dominant inheritance with multi‐generational segregation of pathogenic variants.

ADPKD due to PKD2 exhibits a spectrum of variant classes: missense, nonsense, frameshift, splice‐site, and large rearrangements. A recurrent missense allele, c.83G>C (p.Arg28Pro), has been documented in multiple unrelated families, demonstrating high penetrance and concordant imaging findings (PMID:10417277). Loss‐of‐function mutations predominate, consistent with a haploinsufficiency mechanism.

Clinically, PKD2‐related ADPKD is marked by hypertension (HP:0000822), hematuria, and variable hepatic cyst burden. Cardiovascular manifestations include mitral valve prolapse and aortic aneurysms. Subarachnoid hemorrhage risk is elevated, reflecting vascular fragility in ADPKD patients of both PKD1 and PKD2 genotype (PMID:12842373).

Functional studies demonstrate that the PKD2‐encoded calcium channel, TRPP2, localizes to primary cilia, endoplasmic reticulum, and plasma membrane. Truncated TRPP2 proteins are unstable; missense alleles can impair ciliary trafficking or channel assembly. Aberrant splicing (e.g., IVS8+5G>A) leads to premature stop codons and loss of function, confirmed by RT‐PCR and reduced TRPP2 expression in patient lymphoblasts (PMID:19158373). Mouse models of Pkd2 deficiency recapitulate cystogenesis and cardiac defects via a two‐hit mechanism (PMID:10615132).

Integration & Clinical Utility. The definitive association between PKD2 and ADPKD is supported by segregation in multiple kindreds, robust functional modeling, and concordant histopathology. Genetic testing for PKD2 variants informs prognosis—patients with PKD2 mutations typically reach ESRD ~15–20 years later than PKD1 patients—and guides cascade screening. Identification of truncating PKD2 alleles, including c.83G>C (p.Arg28Pro), supports precise diagnosis and enables risk‐adapted management, blood pressure control, and family counseling.

Key take‐home: PKD2 genotyping provides definitive diagnosis in ~15% of ADPKD patients, predicts a milder course, and underpins tailored clinical surveillance.

References

• Journal of the American Society of Nephrology • 1998 • A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds. PMID:9773786
• American journal of kidney diseases • 2000 • Increased prevalence of polycystic kidney disease type 2 among elderly polycystic patients. PMID:11007674
• American Journal of Human Genetics • 1999 • A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2. PMID:10417277
• Clinical Journal of the American Society of Nephrology • 2009 • Evidence for pathogenicity of atypical splice mutations in autosomal dominant polycystic kidney disease. PMID:19158373
• Nature Genetics • 2000 • Cardiac defects and renal failure in mice with targeted mutations in Pkd2. PMID:10615132
• Lancet • 2003 • Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. PMID:12842373

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