Editing Autosomal dominant polycystic kidney disease (section)

==Genetics==

ADPKD is genetically heterogeneous with two [[genes]] identified: ''[[PKD1]]'' (chromosome region 16p13.3; around 85% cases) <ref>{{Cite journal |last1=Somlo |first1=Stefan |last2=Wirth |first2=Brunhilde |last3=Germino |first3=Gregory G. |last4=Weinstat-Saslow |first4=Debra |last5=Gillespie |first5=Gerald A. J. |last6=Himmelbauer |first6=Heinz |last7=Steevens |first7=Laura |last8=Coucke |first8=Paul |last9=Willems |first9=Patrick |last10=Bachner |first10=Lucien |last11=Coto |first11=Eliecer |last12=López-Larrea |first12=Carlos |last13=Peral |first13=Bélen |last14=Millán |first14=JoséLuis San |last15=Saris |first15=Jasper J. |date=1992-05-01 |title=Fine genetic localization of the gene for autosomal dominant polycystic kidney disease (PKD1) with respect to physically mapped markers |url=https://dx.doi.org/10.1016/0888-7543%2892%2990215-E |journal=Genomics |volume=13 |issue=1 |pages=152–158 |doi=10.1016/0888-7543(92)90215-E |pmid=1349570 |issn=0888-7543}}</ref> and'' [[PKD2]]'' (4q21; around 15% cases).<ref>{{Cite journal |last1=Kimberling |first1=William J. |last2=Kumar |first2=Shrawan |last3=Gabow |first3=Patricia A. |last4=Kenyon |first4=Judith B. |last5=Connolly |first5=Christopher J. |last6=Somlo |first6=Stefan |date=1993-12-01 |title=Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13–q23 |url=https://www.sciencedirect.com/science/article/pii/S0888754311800017 |journal=Genomics |volume=18 |issue=3 |pages=467–472 |doi=10.1016/S0888-7543(11)80001-7 |pmid=8307555 |issn=0888-7543}}</ref><ref>{{Cite journal |last1=Kumar |first1=Shrawan |last2=Kimberling |first2=William J. |last3=Gabow |first3=Patricia A. |last4=Kenyon |first4=Judy B. |date=1991-06-01 |title=Genetic linkage studies of autosomal dominant polycystic kidney disease: search for the second gene in a large Sicilian family |url=https://doi.org/10.1007/BF00204167 |journal=Human Genetics |language=en |volume=87 |issue=2 |pages=129–133 |doi=10.1007/BF00204167 |pmid=1676697 |issn=1432-1203}}</ref><ref name="TP-150518-E20" /> Several genetic mechanisms probably contribute to the [[phenotype|phenotypic]] expression of the disease.<ref name="TP-150518-E20" /> Although  evidence exists for a two-hit mechanism (germline and somatic inactivation of two PKD alleles) explaining the focal development of renal and hepatic cysts,<ref name="TP-150518-E22">{{cite journal | vauthors = Torra R, Badenas C, San Millán JL, Pérez-Oller L, Estivill X, Darnell A | title = A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2 | journal = American Journal of Human Genetics | volume = 65 | issue = 2 | pages = 345–352 | date = August 1999 | pmid = 10417277 | pmc = 1377933 | doi = 10.1086/302501 }}</ref><ref name="TP-150518-E23">{{cite journal | vauthors = Watnick TJ, Torres VE, Gandolph MA, Qian F, Onuchic LF, Klinger KW, Landes G, Germino GG | display-authors = 6 | title = Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease | journal = Molecular Cell | volume = 2 | issue = 2 | pages = 247–251 | date = August 1998 | pmid = 9734362 | doi = 10.1016/s1097-2765(00)80135-5 | doi-access = free }}</ref> [[haploinsufficiency]] is more likely to account for the vascular manifestations of the disease.<ref name="TP-150518-E24">{{cite journal | vauthors = Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Somlo S, Harris PC, Torres VE, Sieck GC | display-authors = 6 | title = Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells | journal = Human Molecular Genetics | volume = 12 | issue = 15 | pages = 1875–1880 | date = August 2003 | pmid = 12874107 | doi = 10.1093/hmg/ddg190 | doi-access = free }}</ref><ref name="TP-150518-E25">{{cite journal | vauthors = Gao Z, Joseph E, Ruden DM, Lu X | title = Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility | journal = The Journal of Biological Chemistry | volume = 279 | issue = 14 | pages = 14225–14231 | date = April 2004 | pmid = 14732716 | doi = 10.1074/jbc.M312223200 | doi-access = free }}</ref> Additionally, new mouse models homozygous for ''PKD1'' hypomorphic alleles 22 and 23 and the demonstration of increased renal epithelial cell proliferation in PKD2 +/− mice suggest that mechanisms other than the two-hit hypothesis also contribute to the cystic phenotype.<ref name="TP-150518-E20" />

Large interfamilial and intrafamilial variability occurs in ADPKD.<ref name="TP-150518-E20" /> Most individuals with ''PKD1'' mutations have kidney failure by age 70 years, whereas more than 50% of individuals with'' PKD2'' mutations have adequate renal function at that age (mean age of onset of end-stage renal disease: 54·3 years with ''PKD1''; 74·0 years with ''PKD2'').<ref name="TP-150518-E26">{{cite journal | vauthors = Hateboer N, v Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL, Torra R, Breuning M, Ravine D | display-authors = 6 | title = Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group | journal = Lancet | volume = 353 | issue = 9147 | pages = 103–107 | date = January 1999 | pmid = 10023895 | doi = 10.1016/s0140-6736(98)03495-3 | s2cid = 30757096 }}</ref>

The significant intrafamilial variability observed in the severity of renal and extrarenal manifestations points to genetic and environmental modifying factors that may influence the outcome of ADPKD, and results of an analysis of the variability in renal function between monozygotic twins and siblings support the role of [[Modifier gene|genetic modifiers]] in this disease.<ref name="TP-150518-E20" /><ref name="TP-150518-E27">{{cite journal | vauthors = Persu A, Duyme M, Pirson Y, Lens XM, Messiaen T, Breuning MH, Chauveau D, Levy M, Grünfeld JP, Devuyst O | display-authors = 6 | title = Comparison between siblings and twins supports a role for modifier genes in ADPKD | journal = Kidney International | volume = 66 | issue = 6 | pages = 2132–2136 | date = December 2004 | pmid = 15569302 | doi = 10.1111/j.1523-1755.2004.66003.x | doi-access = free }}</ref> It is estimated that 43–78% of the variance in age to ESRD could be due to heritable modifying factors,<ref name="TP-150518-E28">{{cite journal | vauthors = Fain PR, McFann KK, Taylor MR, Tison M, Johnson AM, Reed B, Schrier RW | title = Modifier genes play a significant role in the phenotypic expression of PKD1 | journal = Kidney International | volume = 67 | issue = 4 | pages = 1256–1267 | date = April 2005 | pmid = 15780078 | doi = 10.1111/j.1523-1755.2005.00203.x | doi-access = free }}</ref><ref name="TP-150518-E29">{{cite journal | vauthors = Paterson AD, Magistroni R, He N, Wang K, Johnson A, Fain PR, Dicks E, Parfrey P, St George-Hyslop P, Pei Y | display-authors = 6 | title = Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease | journal = Journal of the American Society of Nephrology | volume = 16 | issue = 3 | pages = 755–762 | date = March 2005 | pmid = 15677307 | doi = 10.1681/ASN.2004090758 | doi-access = free }}</ref> with parents as likely as children to show more severe disease in studies of parent-child pairs.<ref name="TP-150518-E20" /><ref name="TP-150518-E30">{{cite journal | vauthors = Geberth S, Ritz E, Zeier M, Stier E | title = Anticipation of age at renal death in autosomal dominant polycystic kidney disease (ADPKD)? | journal = Nephrology, Dialysis, Transplantation | volume = 10 | issue = 9 | pages = 1603–1606 | year = 1995 | pmid = 8559477 }}</ref>