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| ==Pathophysiology== | | ==Pathophysiology== |
| Recent studies in fundamental cell biology of [[cilia]]/[[flagella]] using experimental [[model organisms]] like the green algae ''[[Chlamydomonas]]'', the round worm ''[[Caenorhabditis elegans]]'' and the mouse ''[[Mus musculus]]'' have shed light on how PKD develops in patients. All [[cilia]] and [[flagella]] are constructed and maintained, including localizing of proteins inserted into ciliary and flagellar membranes, by the process of [[intraflagellar transport]]. Environmental sensing and cellular signaling pathways initiated from proteins inserted into ciliary/flagellar membranes are thought to be critical for normal renal cell development and functioning. Membrane proteins which function in developmental and physiological environmental sensing and intracellular signalling are sorted to and localized to the cilia in renal epithelial cells by [[intraflagellar transport]]. These epithelial cells line the lumen of the urinary collecting ducts and sense the flow of urine. Failure in flow-sensing signaling results in programmed cell death or [[apoptosis]] of these renal epithelial cells producing the characteristic multiple cysts of PKD. PKD may result from mutations of signaling and environmental sensing proteins, or failure in [[intraflagellar transport]]. Two PKD genes, ''PKD1'' and ''PKD2'', encode membrane proteins which localize to a non-motile cilium on the renal tube cell. Polycystin-2 encoded by ''PKD2'' gene is a calcium channel which allows extracellular calcium ions to enter the cell. Polycystin-1, encoded by ''PKD1'' gene, is thought to be associated with polycystin-2 protein and regulate its channel activity. The calcium ions are important cellular messengers which, in turn, trigger complicated biochemical pathways which lead to quiescence and differentiation. Malfunctions of polycystin-1 or polycystin-2 proteins, defects in the assembly of the cilium on the renal tube cell, failures in targeting these two proteins to the cilium, and deregulations of calcium signaling all likely cause the occurrence of PKD.
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| '''PKD and the "two hit" hypothesis:'''
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| The two hit hypothesis (aka [[Knudson hypothesis]] ) is often used to explain the manifestation of polycystic kidney disease later in life even though the mutation is present at birth. This term is borrowed from cancer research stating that both copies of the gene present in the genome have to be "silenced" before cancer manifests itself (in Knudson's case the silenced gene was ''Rb1''). In ADPKD the original "hit" is congenital (in either the ''PKD1'' or ''PKD2'' genes) and the subsequent "hit" occurs later in life as the cells grow and divide. The two hit hypothesis as it relates to PKD was originally proposed by Reeders in 1992.<ref>{{cite journal |author=Reeders ST |title=Multilocus polycystic disease |journal=Nat. Genet. |volume=1 |issue=4 |pages=235-7 |year=1992 |pmid=1338768 |doi=10.1038/ng0792-235}}</ref> Support for this hypothesis comes from the fact that ARPKD patients develop disease at birth, and [[Mutation|somatic mutations]] in the "normal" copy of ''PKD1'' or ''PKD2'' have been found in cyst-lining [[epithelia]]
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| ===Genetics===
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| The disease exists both in an [[autosomal recessive]] and an [[autosomal dominant]] form.
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| ====Autosomal dominant form====
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| The autosomal dominant form, called ADPKD (autosomal dominant PKD or "Adult-onset PKD") is much more common but less severe. In 85% of patients, ADPKD is caused by [[mutation]]s in the [[gene]] ''[[PKD1]]'' on chromosome 16 (TRPP1); in 15% of patients mutations in ''[[PKD2]]'' (TRPP2) are causative. A third locus ''PKD3'' is the cause of a very small percentage of cases.
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| * {{OMIM|173910}}, {{DiseasesDB|10262}}
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| [[Image:Autodominant.jpg|thumb|left|150px|ADPKD is inherited in an [[autosomal dominant]] pattern.]]
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| ====Autosomal recessive form====
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| The recessive form, called ARPKD (autosomal recessive polycystic kidney disease) is the less common variant. Mutations in the ''[[PKHD1]]'' (chromosomal locus 6p12.2) cause ARPKD.
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| * {{OMIM|263200}}, {{DiseasesDB|10280}}
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| [[Image:autorecessive.jpg|thumb|left|150px|ARPKD is inherited in an [[Recessive gene|autosomal recessive]] pattern.]]
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| ====Other types====
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| A small number of families with polycystic kidney disease do not have apparent mutations in any of the three known genes. An unidentified gene or genes may also be responsible for this disease. In this case, the disease is designated "PKD3".
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| ===Gross Pathology===
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| [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
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| [[Image:Infantile polycystic disease.jpg|thumb|left|350px|Infantile polycystic disease: Gross natural color view of both kidneys with ureters and uterus (very good example) ]]
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| ===Associated conditions===
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| *[[Aortic aneurysm]]
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| *[[Berry aneurysm]]
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| *[[Subarachnoid hemorrhage]]
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| *[[Cyst]]s in [[liver]], [[pancreas]], [[testes]]
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| *[[Diverticula]] in [[colon]]
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| *[[Myotonic dystrophy]]
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| *[[Tuberous sclerosis]]
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| *[[Portal hypertension]]
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| *Salt losing nephropathy
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| ==References== | | ==References== |