PKD Epidemiology – Journal Club

ADPKD

• Inherited
• Fluid filled cysts in kidney and occasionally liver and pancreas
• Deterioration in renal function due to compression of the renal parenchyma
• Heterozygous variant located in the PKD1 gene with a nonsense single nucleotide polymorphism in exon 29 (chrE3:g.42858112C>A, the conventional PKD1 variant).
• This variant causes a stop codon, truncating the protein up to 25% at the c-terminus
• Homozygous lethal in the embryonic stage
• PKD1 encodes polycystin 1 (PC1), which is a membrane-bound large multi-domain glycoprotein with a G protein couples receptor proteolytic site
• Physiological function is unclear; located on the primary cilia, a flagellar organelle protruding from the cell surface used for mechanotransduction
• PC1 I s thought to perform an important role in transmitting signals from outside the cell
• The loss of functional PC1 appears to contribute to the cystogenesis n ADPKD and much research has been conducted to identify the underlying mechanisms
• Proposed the influence of various upregulated or down regulated intracellular signals while others have said that macrophage recruitment by the primary cilia plays a huge role in cytogenesis
• 2 models of the relationship between PC1 dsage and cystogenesis have been established
• 2 – hit model :After inactivation of one allele by germiline mutation , a somatic mutation occurs , inactiviating the other allele and thereby causing cystogenesis
• Threshold theory : more recent suggests that the disease occurs when the PC1 levels drop below a certain threshold and do not necc, have to be at zero
• Since the variant responsible for the feline ADPKD truncates PC1 it can be assumed that the truncated abnormal protein is unable to function properly , leading to a lack of functional PC1
• Genetic tests to identify the PKD1 gene but cant predict the severity of disease or evaluate progression
• Persian and related breeds
• In Japan also seen in Scottish folds and American SHorthiar
• Prevenlence in few studies reported as 13.5% in China, 33% in Slovenia 40$ in Japan -> mostly focused on persian cats or cats suspected of CKD – small numbers of cats
• No data on cat population as a whole regarding prevalence of the disease or the PKD1 gene
• Some studies have revealed that cats without the conventional PKD1 variant can develop ADPKD – suggests that an unknown variant may severe as another cause of ADPKD