TY - JOUR
T1 - A potentially crucial role of the PKD1 C-terminal tail in renal prognosis
AU - Higashihara, Eiji
AU - Horie, Shigeo
AU - Kinoshita, Moritoshi
AU - Harris, Peter C.
AU - Okegawa, Takatsugu
AU - Tanbo, Mitsuhiro
AU - Hara, Hidehiko
AU - Yamaguchi, Tsuyoshi
AU - Shigemori, Kaori
AU - Kawano, Haruna
AU - Miyazaki, Isao
AU - Kaname, Shinya
AU - Nutahara, Kikuo
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Background Autosomal dominant polycystic disease (ADPKD) often results in renal failure. Recently, allelic influences of PKD1 mutation types on renal survival were extensively investigated. Here, we analyzed integrated influences of PKD1 mutation types and positions on renal survival. Methods We included 338 (82 pedigrees) and 72 (12 pedigrees) patients with PKD1 and PKD2 mutations, respectively, identified through comprehensive gene analysis of 101 probands with ADPKD. Genetic testing was performed using next-generation sequencing, long-range PCR, and multiplex ligation-dependent probe amplification. Pathogenic mutations were identified by a software package-integrated seven databases and provided access to five cloud-based computing systems. Results Mean renal survivals of carriers with PKD1 non-truncating-type mutations at positions upstream of G-protein-coupled receptor proteolytic site (GPS-upstream domain), transmembrane domain, or cytoplasmic C-terminal tail (CTT) domain were 70.2, 67.0, and 50.1 years, respectively (P \ 0.0001); renal survival was shorter for mutation positions closer to CTT domain, suggesting its crucial role in renal prognosis. Furthermore, in truncating-type mutations, strong inactivation is anticipated on nucleotides downstream from the mutation site, implying CTT domain inactivation irrespective of mutation site. Shorter mean renal survival was found for PKD1 truncating-type than non-truncating-type mutation carriers (P = 0.0348); mean renal survival was not different between PKD1 30 - and 50 -region truncating-type mutation carriers (P = 0.4375), but was shorter in PKD1 30 -region than in 50 -region non-truncating-type mutation carriers (P = 0.0014). Variable strength of CTT domain inactivation might account for these results. Conclusions Aforementioned findings indicate that CTT domain’s crucial role in renal prognosis needs further investigation by larger studies (ClinicalTrials.gov; NCT02322385).
AB - Background Autosomal dominant polycystic disease (ADPKD) often results in renal failure. Recently, allelic influences of PKD1 mutation types on renal survival were extensively investigated. Here, we analyzed integrated influences of PKD1 mutation types and positions on renal survival. Methods We included 338 (82 pedigrees) and 72 (12 pedigrees) patients with PKD1 and PKD2 mutations, respectively, identified through comprehensive gene analysis of 101 probands with ADPKD. Genetic testing was performed using next-generation sequencing, long-range PCR, and multiplex ligation-dependent probe amplification. Pathogenic mutations were identified by a software package-integrated seven databases and provided access to five cloud-based computing systems. Results Mean renal survivals of carriers with PKD1 non-truncating-type mutations at positions upstream of G-protein-coupled receptor proteolytic site (GPS-upstream domain), transmembrane domain, or cytoplasmic C-terminal tail (CTT) domain were 70.2, 67.0, and 50.1 years, respectively (P \ 0.0001); renal survival was shorter for mutation positions closer to CTT domain, suggesting its crucial role in renal prognosis. Furthermore, in truncating-type mutations, strong inactivation is anticipated on nucleotides downstream from the mutation site, implying CTT domain inactivation irrespective of mutation site. Shorter mean renal survival was found for PKD1 truncating-type than non-truncating-type mutation carriers (P = 0.0348); mean renal survival was not different between PKD1 30 - and 50 -region truncating-type mutation carriers (P = 0.4375), but was shorter in PKD1 30 -region than in 50 -region non-truncating-type mutation carriers (P = 0.0014). Variable strength of CTT domain inactivation might account for these results. Conclusions Aforementioned findings indicate that CTT domain’s crucial role in renal prognosis needs further investigation by larger studies (ClinicalTrials.gov; NCT02322385).
KW - Autosomal dominant polycystic kidney disease (ADPKD)
KW - Genotype/phenotype correlation
KW - PKD1 mutation
KW - Renal survival
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U2 - 10.1007/s10157-017-1477-7
DO - 10.1007/s10157-017-1477-7
M3 - Article
C2 - 28983800
SN - 1342-1751
VL - 22
SP - 395
EP - 404
JO - Clinical and Experimental Nephrology
JF - Clinical and Experimental Nephrology
IS - 2
ER -