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Autosomal Dominant Polycystic Kidney Disease with Anticipation and Caroli's Disease Associated with a PKD1 Mutation Rapid Communication

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Autosomal Dominant Polycystic Kidney Disease with Anticipation and Caroli's Disease Associated with a PKD1 Mutation Rapid Communication CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Kidney International, Vol. 52 (1997), pp.33—38 Autosomal dominant polycystic kidney disease with anticipation and Caroli's disease associated with a PKD1 mutation Rapid Communication ROSER Toiu&, CELIA BADENAS, ALEJANDRO DARNELL, CoNcEPcIO BRi, ANGELS ESCORSELL, and XAVIER ESTIVILL Nephrology Service, Genetics Service, Sonography Section of the Radiology Service, and Hepatology Service, Hospital ClInic, Barcelona, Spain Autosomal dominant polycystic kidney disease with anticipation and (ESRD) than PKD1 patients [14]. The PKD1 transcript consists Caroli's disease associated with a PKD1 mutation. Autosomal dominant of 14,148 bp, distributed among 46 exons, spanning 52 kb. An polycystic kidney disease (ADPKD) is the most common renal hereditary interesting feature of this gene is that all but 3.5 kb at the 3'end disorder. Clinical expression of ADPKDshowsinterfamilial and intrafa- milial variability. We screened for mutations the 3' region of the PKD1 of the transcript is encoded by a region repeated several times, gene, from exon 43 to exon 46, in a family showing anticipation and proximally in the same chromosome. Until now very few muta- Caroli's disease and have found a 28 base pairs deletion in exon 46tions [15—19] have been reported in the PKDI gene, mainly due to (12801de128) and a new DNA variant in exon 43 (12184 C to G conserving the this fact, and most of them are located in the non-repeated Ala 3991) segregating with the disease. The mutation should result in a3'region. Only one of these mutations has been reported in more protein 44aminoacids longer than the wild-type PKD1. This PKDI mutation manifests as typical adult-onset disease in the father, but in the than one family [20]. proband, a 26-year-old man, ADPKD was diagnosed as a newborn and The presence of anticipation, defined as beginning of ESRD at was associated with Caroli's disease at the age of 18 years. A renal biopsy least ten years earlier in the offspring than in the parent or the performed in childhood disclosed a predominance of glomerular cysts. Mutation 12801de128 is the first molecular defect associated with Caroli's presence of early-onset cases in a family, has been reported in disease and the PKD1 phenotype. The finding of the same mutation in two several ADPKD families [2, 14, 211. There is no molecular basis to different members of the same family with different expression of theexplain anticipation in ADPKD. The PKD1 gene has been fully disease indicates that the phenotypic variation in ADPKD must be due to sequenced and there are no trinucleotide repeats larger than five modifying factors that may radically affect the course of the disease. copies that could explain the phenomenon of anticipation as has been found in some neurological disorders [22]. Hepatic involvement is extremely frequent in ADPKD. It Autosomal dominant polycystic kidney disease (ADPKD) is theusually presents as polycystic liver disease (PLD), being more most common renal inherited disorder affecting 1 in 1000 personsfrequent as the age increases, and it is more severe in women [23, [1] and accounting for 10% of patients on renal replacement24]. PLD belongs to a family of liver diseases, characterized by an therapy (RRT) [21. It is characterized by the progressive renal cystovergrowth of biliary epithelium and supportive connective tissue, development and enlargement as well as a wide array of extrare-called the hepatobiliary fibropolycystic diseases [25]. These disor- nal features [31. Several reports reveal a high intrafamilial andders include dilation of the extrahepatic and/or intrahepatic bile interfamilial variability of the clinical expression of the disease [4,ducts, segmental dilatation of intrahepatic bile ducts (Caroli's disease), congenital hepatic fibrosis, autosomal recessive polycys- 51. At least three different genes may cause ADPKD: PKD1, intic kidney disease (ARPKD) and PLD. The common pathogenesis chromosome lopl3.3 [61 accounts for about 85% of the cases [7],for these entities may explain why the presence of these diseases PKD2at4q13 to 23 [8—10] accounts for the remaining 15% and afrequently overlaps. Hepatic fibrosis is always present in ARPKD third locus still unmappcd causes the disease in some reportedbut it is rare in ADPKD [26]; moreover, Caroli's disease is quite families [1 1—13]. PKD2 has been proved to be a milder form of the frequent in ARPKD [27, 28] but extremely infrequent in ADPKD disease with a later age of onset of end-stage renal disease[29—32]. Here we describe a deletion of 28 bp in the PKDJ gene in two members of the same family showing different expression of the disease: a severely affected young adult with ADPKD and Caroli's Key words: ADPKD, intrafamilial variability, hepatic disease, early onset, disease diagnosed as a newborn, and his father who has typical glomerular cysts. adult onset ADPKD. Received for publication January 25, 1997 and in revised form March 3, 1997 METHODS Accepted for publication March 3, 1997 Genomic DNAfrom150 unrelated individuals was extracted © 1997 by the International Society of Nephrology with the salting out method [33] and was amplified with several 33 34 Torra et al: PKD1 mutation, anticipation and Caroli's disease S i (I l.*-< Fig. 1. Renal biopsy of the proband at two months of age. Preserved renal tissue can be found among tubular and glomerular cysts. An is"--- arrow points a glomerular cyst. primers that covered the DNA sequence from exon 43 to exon 46.ocrit 37%, platelets 39,000 per mm3 and prothrombin test 69%. The results in the present work were obtained with primers JJThe sonography scan disclosed hepatomegaly with dilation of (12666-12848 nt of PKD1 eDNA; exon 46) using a DMSOintrahepatic bile ducts preferentially in the right lobe (Fig. 2), containing buffer and annealing at 60°C with 1.5 mi MgC12 andportal cavernomatosis, splenomegaly and cystic kidneys of 17 cm with primers DD (12084-12271 nt of PKDJ cDNA; exons 43 to 44) of diameter. Delayed views of a hepatobiliary scintigraphy 99mTc with the same buffer and PCR conditions as JJ [171. The productsDISIDA (diisopropyliminodiacetic acid) demonstrated retained of 183 bp and 263 bp, respectively, were analyzed by SSCA (single radiotracer, at 24-hours post-injection, preferentially in the right strand conformation analysis) with the silver staining techniquelobe. [341. The abnormal PCR fragments generated were sequenced The father is 53 years old and has polycystic liver and renal using ABI PRISM Dye Terminator Cycle Sequencing Readydisease. He has been on RRT for the last three months. The Reaction Kit in an ABI PRISM Genetic Analyzer 310 (Perkinmother and the brother (24-years-old) showed no evidence of Elmer, Foster City, KS, USA). Microsatellites AC25-D16S291,ADPKD either clinically or at ultrasound. Two uncles were KG8-PKE1 and CW2-D16S663 were amplified and analyzed asdiagnosed with ADPKD and started RRT at the age of 60 and 58, previously described [14J. The Gene Bank accession number ofrespectively. The grandfather and the great-grandfather died at 58 the cDNA sequence used to number the nucleotides position isand 50 years of age, respectively, due to uremia. L33243. Molecular analysis RESULTS Linkage analysis using three microsatellites from the PKDJ region Clinical data (AC2.5-D16S291, KG8-PKD1 and CW2-D16S663) showed that the The proband is a 26-year-old man who was diagnosed as aparent had transmitted different alleles to his two sons (Fig. 3a). newborn of polycystic kidney disease due to palpation of enlarged The 3' end of the PKDJ genomic sequence of the father was kidneys. A renal biopsy, performed at two months of age, dis-analyzed for mutations by SSCA and an abnormal fragment was closed a renal surface covered by multiple cysts of 5 mm ofdetected with the primers JJ [17]. As the SSCA pattern suggested diameter. Microscopical analysis showed multiple cysts of aa deletion the PCR product was electrophoresed in a 4% agarose uniform size limited by cuboidal epithelium and separated bygel where two fragments of 183 and 155 bp could be seen in the scarce intercellular matrix in which renal tubuli and glomeruliaffected individuals and only one fragment of 183 bp in normal were embedded. There were also some cystic glomeruli (Fig. 1).subjects. Only the father and the affected son have the mutation He did not follow any medical control until the age of 18 years(Fig. 3b). Direct sequencing showed a 28 bp deletion (12801del28) when in a routine analysis pancitopenia was discovered. Panci-in exon 46 (Fig. 3c). This mutation induces a frameshift after topenia was attributed to portal hypertension diagnosed in hemo-amino acid 4200 and should result in a protein 44 amino acids dynamic studies. The cause of portal hypertension was supposedlonger than the normal PKDJ protein. The mutation 12801de128 to be either Caroli's disease associated with liver fibrosis or portalwas not detected in a further screen of 150 normal chromosomes. cavernomatosis, which were both present in the patient. At the Another abnormal fragment in the SSCA was found with age of 23 a slight deterioration of the renal function was discov-primers DD. Direct sequencing showed a C to G transition (12184 ered and a renal sonography disclosed enlarged cystic kidneys. C to G conserving Ala 3991) in exon 43. The same abnormal band At the time of the study, the creatinine was 4 mg/dl, thewas present in the affected son (Fig. 3a). This change was not seen creatinine clearance 20 ml/min, leukocytes 1400 per mm3, hemat-in a further study of 300 chromosomes. Ton-a et al: PKDI mutation, anticipation and Caroli's disease 35 -- — -a-I- Fig. 2. Sonography image of the right lobe of the liver showing tubular (up) and sacular t (down) dilation of the intrahepatic bile ducts.
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