Polycystic Kidney Disease (PKD)

Polycystic kidney disease (PKD)     This condition involves the growth of numerous cysts in the kidneys. Common symptoms and signs include: o Pain o UTIs o Haematuria o Liver and pancreatic cysts o Abnormal heart valves o High blood pressure o Kidney stones o Aneurysms o Diverticulosis Diagnosis involving trans-abdominal ultrasound scanning: o < 30 years – presence of at least 2 renal cysts (unilateral or bilateral) o 30-59 years – presence of at least 2 cysts in each kidney o > 60 years – at least 4 cysts in each kidney Autosomal dominant PKD involves mutations in PKD1 and PKD2. Approximately 85% of ADPKD patients have mutations in PKD1. All affected people should have an affected parents, where the chance of an affected person having an affected child is 50%. o PKD1 (16p13.3 = the gene located on the short arm of chromosome 16 at region 13.3) – located on chromosome 16, polycystin-1 is an integral membrane glycoprotein involved in cell-to-cell and/or cell-to-matrix interaction and functions as a mechanosensor o PKD2 (4q21–q23) – located on chromosome 4, the polycystin-2 function as a calcium ion channel, regulating calcium influx and/or release from intracellular stores Autosomal recessive PKD involves mutations in PKHD1 (6p21.1–p12). This form of the disease tends to skip generations, where the chance of two unaffected carriers having an affected child is 25% One hit vs. two hit hypothesis       As we age, our cells accumulate mutations in its DNA such as by exposure to environmental agents or imperfect DNA replication If those cells with mutations go through mitosis and divide, they will pass that mutation on to its daughter cells In order to develop a cyst, you need to mutate both alleles in the cell so that you can’t produce functional PKD protein (for example) In the two hit model, you need to mutate both alleles in the cell in order to produce a cyst For an individual who has inherited a mutation in PKD1 (for example), every cell in the kidney already has one allele that is mutated. Thus, everytime they get a mutation in their healthy allele, the patient will develop a cyst (since both alleles are now mutated) = one hit model In PKD the original "hit" is congenital (in either PKD1 or the PKD2 genes) and the subsequent "hit" occurs later in life as the cells grow and divide. The evidence is based on that the PKD patients develop disease at birth, and somatic mutations in the "normal" copy of the PKD1 or PKD2 have been found in cyst-lining epithelia Type of mutations: Nonsense Frameshifting Inframe Splicing Missense Frequency: PKD1 33% 28% 6% 14% 19% PKD2 37% 39% 17% 6% 1% Review of mutations      Nonsense mutation = when new nucleotide changes a codon that specified an amino acid to one of the STOP codons (TAA, TAG, or TGA). Frameshift mutation = add or remove one or two nucleotides to change the amino acid sequence from the site of the mutation. Inframe mutation = does not cause a shift in the triplet reading frame but can lead to the synthesis of an abnormal protein product. Missense mutation = a single base pair substitution that results in the translation of a different amino acid at that position Splicing = nucleotide signals at the splice sites guide the enzymatic machinery (if a mutation alters one of these signals, either intron is not removed and remains as part of final RNA molecule, or exon is spliced out) Pathogenesis of PKD   The proteins made from the genes discussed before (PKD1, PKD2) are called polycystins (these proteins are mainly concentrated in primary cilium of kidney epithelial cells) o Polycystin-1: confined to epithelial cells in kidney o Polycystin-2: found in most cysts of polycystic kidneys The primary cilium of a mouse kidney epithelial cell acts as an antenna, sensing fluid flow. The shear stress from the bending cilium activates polycystin-1, which signals polycystin-2, a calcium channel, to allow calcium into the cell. This influx activates intracellular ryanodine receptors, releasing additional calcium from pools in the cell. The amplified signal plays a role in regulating processes related to tissue development (though the exact mechanism is still not fully understood)  Cytogenesis: cysts arise as an outpouching from the renal tubule, due to excessive proliferation of tubular cells. As cysts enlarge, their connection with the nephron is lost, and they are disconnected from the tubule and enlarge as independent structures  How disruption of cilia leads to cyst formation : in normal kidneys, renal tubules come very close to terminal differentiation (know what their role is). However, after the 2nd mutation they revert to a more immature phenotype (‘dedifferentiation’), where the tubules take on roles that they don’t need to do i.e. becomes a cell that starts dividing. Cilia bending increase the Ca2+ concentration in cell and neighbouring cells. Ligands attaching to normal polycystins result in a “stop signal” and a lack of sensing alters gene transcription (as no signal is sent to cell to stop dividing because the polycystins are mutated). Thus the cells become dedifferentiated and it leads to uninhibited growth