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Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.

ABSTRACT: Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0?Mb) and large CNVs (>1.0?Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.

SUBMITTER: Wills ES

PROVIDER: S-EPMC5117941 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.

Wills Edgar S ES Cnossen Wybrich R WR Veltman Joris A JA Woestenenk Rob R Steehouwer Marloes M Salomon Jody J Te Morsche René H M RH Huch Meritxell M Hehir-Kwa Jayne Y JY Banning Martijn J MJ Pfundt Rolph R Roepman Ronald R Hoischen Alexander A Drenth Joost P H JP

European journal of human genetics : EJHG 20160824 12

Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions us ...[more]

PMID: 27552964

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Project description:Background and objectivesWe have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort.Design, setting, participants, and measurementsComprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019.Results and conclusionsOf the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was -1.6 ml/min/1.73 m2/y, in comparison to -0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20-25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the "medullary" to the "corticomedullary" group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.

Project description:Background & aimsPolycystic liver disease (PLD) is characterised by increased autophagy and reduced miRNA levels in cholangiocytes. Given that autophagy has been implicated in miRNA regulation, we tested the hypothesis that increased autophagy accounts for miRNA reduction in PLD cholangiocytes (PLDCs) and accelerated hepatic cystogenesis.MethodsWe assessed miRNA levels in cultured normal human cholangiocytes (NHCs), PLDCs, and isolated PLDC autophagosomes by miRNA-sequencing (miRNA-seq), and miRNA targets by mRNA-seq. Levels of miR-345 and miR-345-targeted proteins in livers of animals and humans with PLD, in NHCs and PLDCs, and in PLDCs transfected with pre-miR-345 were assessed by in situ hybridisation (ISH), quantitative PCR, western blotting, and fluorescence confocal microscopy. We also assessed cell proliferation and cyst growth in vitro, and hepatic cystogenesis in vivo.ResultsIn total, 81% of miRNAs were decreased in PLDCs, with levels of 10 miRNAs reduced by more than 10 times; miR-345 was the most-reduced miRNA. In silico analysis and luciferase reporter assays showed that miR-345 targets included cell-cycle and cell-proliferation-related genes [i.e. cell division cycle 25A (CDC25A), cyclin-dependent kinase 6 (CDK6), E2F2, and proliferating cell nuclear antigen (PCNA)]; levels of 4 studied miR-345 targets were increased in PLDCs at both the mRNA and protein levels. Transfection of PLDCs with pre-miR-345 increased miR-345 and decreased the expression of miR-345-targeted proteins, cell proliferation, and cyst growth in vitro. MiR-345 accumulated in autophagosomes in PLDCs but not NHCs. Inhibition of autophagy increased miR-345 levels, decreased the expression of miR-345-targeted proteins, and reduced hepatic cystogenesis in vitro and in vivo.ConclusionAutophagy-mediated reduction of miR-345 in PLDCs (i.e. miRNAutophagy) accelerates hepatic cystogenesis. Inhibition of autophagy restores miR-345 levels, decreases cyst growth, and is beneficial for PLD.Lay summaryPolycystic liver disease (PLD) is an incurable genetic disorder characterised by the progressive growth of hepatic cysts. We found that hepatic cystogenesis is increased when the levels of miR-345 in PLD cholangiocytes (PLDCs) are reduced by autophagy. Restoration of miR-345 in PLDCs via inhibition of autophagy decreases hepatic cystogenesis and thus, is beneficial for PLD.

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Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.

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Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes.

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