Polycystic Kidney Disease (PKD) • • Growth of numerous cysts in kidneys Symptoms: pain, UTIs, haematuria, liver and pancreatic cysts, abnormal heart valves, high blood pressure, kidney stones, aneurysms, diverticulitis Diagnosis: • • • • Trans-abdominal ultrasound scan <30 years: presence of at least 2 renal cysts (unilateral or bilateral) 30-59 years: presence of at least 2 cysts in each kidney >60 years: at least 4 cysts in each kidney Genetics of PKD • Autosomal dominant (AD) o PKD1 (16p13.3): 46 exons o PKD2 (4q21-q23): 15 exons o Approximately 85% of ADPKD have mutations in PKD1 • Autosomal recessive (AR) o PKHD1 • Mutations are mostly nonsense and frameshifting “Two-Hit” Method: In every kidney cell, there are two alleles for each ADPKD gene. There needs to be 2 mutations, one on each allele, to make that cell into a cyst – hence, “two-hit”. Whereas in PKD, the patient has inherited one mutated allele in every kidney cell and hence only needs one mutation to produce a cyst. In ARPKD, you inherit two fault alleles. Splicing • Nucleotide signals at the splice sites guide the enzymatic machinery  If a mutation alters one of these signals, then: o The intron is not removed and remains as part of the RNA sequence, or: o An exon is spliced out o Therefore, either error will produce a different protein product • • • PKD1  Polycystin 1 (PC1):epithelial cells of kidneys PKD2 Polycystin 2 (PC2): found in most cysts of PKD These genes are highly expressed in the DCT Cystogenesis Outpouching from renal tubule due to increased cell proliferation Cyst grows and detaches from renal tubule Cilia detect tubular fluid flow: sheer stress  cilia bending  PC1 activates  PC2 Ca channel opens allowing Ca into cell  activates ryanodine receptors  Ca release from calcium pool  unknown process  changed cell function • Note: ARVD (arrthythmogenic right ventricular cardiomyopathy) is caused by a mutation in the gene coding for the ryanodine receptor • • • Mutated Polycystins • • Tubular cells come very close to terminal differentiation After 2nd mutation, tubular cells revert to their immature phenotype and they will remain as this phenotype • • Polycystins are thus implicated as growth suppressors Therefore, if polycystins are mutated, they can’t suppress cell growth, which leads to the development of a cyst  Mechanism: o Cilia bending  ↑Ca concentration in cell and adjacent cells o Ligands attaching to normal polycystins results in stop signal o Lack of sensing  changes genetic expression o Cells become dedifferentiated o Leads to uninhibited growth  cyst