Patients with Protein-Truncating PKD1 Mutations and Mild ADPKD

Abstract

Background and objectivesProgression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized.Design, setting, participants, & measurementsFrom the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR.ResultsAmong 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A–1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A–1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability.ConclusionsDespite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3

Recessive PKD1 Mutations Are Associated With Febrile Seizures and Epilepsy With Antecedent Febrile Seizures and the Genotype-Phenotype Correlation

“…Previously reported PKD1 mutations were mainly associated with ADPKD. From the genotype aspect, ADPKD-associated PKD1 mutations were mainly monoallelic, and majority of the mutations were destructive ( Sandford, 2009 ; Cornec-Le Gall et al, 2014 ; Lanktree et al, 2021 ), implying that monoallelic mutations with haploinsufficiency of PKD1 potentially caused kidney disease. Less commonly, truncating PKD1 mutations were identified in families ADPKD ( Lanktree et al, 2021 ).…”

“…From the genotype aspect, ADPKD-associated PKD1 mutations were mainly monoallelic, and majority of the mutations were destructive ( Sandford, 2009 ; Cornec-Le Gall et al, 2014 ; Lanktree et al, 2021 ), implying that monoallelic mutations with haploinsufficiency of PKD1 potentially caused kidney disease. Less commonly, truncating PKD1 mutations were identified in families ADPKD ( Lanktree et al, 2021 ). Homozygotes of PKD1 mutations caused severe phenotype with in utero onset ADPKD or premature neonate death ( Cornec-Le Gall et al, 2018 ; Al-Hamed et al, 2019 ; Garel et al, 2019 ; Durkie et al, 2021 ), consistent with the embryonic lethality in homozygous Pkd1 knockout mice ( Lu et al, 2001 ; Lantinga-van Leeuwen et al, 2007 ).…”

The Evolving Role of Diagnostic Genomics in Kidney Transplantation

“…Compared with patients with PKD2 , those with PKD1 gene mutations progress to KF on average 20 years earlier and die at a younger age. 64 Importantly, up to 18% of affected individuals might experience significant intrafamilial disease variability 65 compared with that anticipated by their genotype and/or family history.…”

PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression

“…Supporting the gene dosage model,'second hit' mutations do not appear to be a universal feature, especially in smaller ADPKD cysts [4][5][6][7] . Importantly, many individuals with ADPKD continue to have residual PC1 expression because they carry missense (rather than inactivating) germline PKD1 mutations 8,9,10 . As proof of principle, lowering the Pkd1 dose is sufficient to produce PKD in mice, pigs, and monkeys 4,[11][12][13][14][15][16] .…”