Polycystic kidney disease causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Serge Korjian, Yazan Daaboul

Polycystic kidney disease is a genetic disorder. Autosomal dominant polycystic kidney disease (ADPKD) is an autosomal dominant disorder due to the heterozygous inheritance of PKD1 (chromosome 16) or PKD2 (chromosome 4) gene mutations. Despite the disease being monogenic, phenotype is variable possibly due to a two-hit process, haploinsufficiency, or environmental factors. Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene.

• Autosomal dominant polycystic kidney disease (ADPKD) is caused by a mutation in either the PKD1 gene or PKD2 gene.^[1]
• ADPKD is an inherited disorder with 2 possible etiologic mutations.
• PKD1 mutations found on short arm of chromosome 16 (16p13.3) accounts for roughly 85% of cases.^[2]
• PKD2 mutations found on the long arm of chromosome 4 (4q21) account for 15% of the remaining cases.^[3]
• All cases of ADPKD are heterozygous for either PKD mutations or both.
• Homozygous cases usually die in utero.^[4]
• Generally, PKD1 mutants have more severe renal disease with mean age at onset of ESRD around 50 years compared to 75 years in PKD2 mutants.^[5]
• Patients heterozygous for both mutations have the most severe renal manifestations.
• Despite the monogenic nature of the disease, the phenotype and severity of the disease as well as the extrarenal manifestations have been known to vary even within the same family.
• Several mechanisms have been proposed to explain this variability including:^[6]
  • A two-hit hypothesis involving loss of two PKD alleles in both germline and somatic cell lines
  • Haploinsufficiency
  • Environmental factors modifying disease processes
• Autosomal recessive polycystic kidney disease (ARPKD) is caused by a mutation in the PKHD1 gene^[7][8]
  • PKHD1 is a gene that shares structural similarities with the hepatocyte growth-factor receptor.
• Genotype-phenotype correlation studies show that truncated PKD1 variants are associated with more severe disease when compared to PKD1 missense and PKD2 variants.
• Recently several genes have been implicated in rare cases of ADPKD.These include  IFT140, GANAB, NEK8, and DNAJB11 .

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