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Type of PKD1 Mutation Influences Renal Outcome in ADPKD

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Type of PKD1 Mutation Influences Renal Outcome in ADPKD CLINICAL RESEARCH www.jasn.org Type of PKD1 Mutation Influences Renal Outcome in ADPKD † †‡ †‡ Emilie Cornec-Le Gall,* Marie-Pierre Audrézet, Jian-Min Chen, Maryvonne Hourmant,§ | †† Marie-Pascale Morin, Régine Perrichot,¶ Christophe Charasse,** Bassem Whebe, ‡‡ || † Eric Renaudineau, Philippe Jousset,§§ Marie-Paule Guillodo, Anne Grall-Jezequel,* †‡ †‡ † Philippe Saliou, Claude Férec, and Yannick Le Meur* *Nephrology Department, University Hospital, Brest, France; †Université de Bretagne Occidentale and European University of Brittany, Brest, France; ‡Molecular Genetic Department, INSERM U1078, University Hospital, EFS- Bretagne, Brest, France; §Nephrology Department, University Hospital, Nantes, France; |Nephrology Department, University Hospital, Rennes, France; ¶Nephrology Department, Vannes Hospital, Vannes, France; **Nephrology Department, Saint Brieuc Hospital, Saint Brieuc, France; ††Nephrology Department, Quimper Hospital, Quimper, France; ‡‡Nephrology Department, Broussais Hospital, Saint Malo, France; §§Nephrology Department, Pontivy Hospital, Pontivy, France; and ||Association des Urémiques de Bretagne, Brest, France ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value. J Am Soc Nephrol 24: 1006–1013, 2013. doi: 10.1681/ASN.2012070650 Autosomal dominant polycystic kidney disease patients with PKD1 than those with PKD2,6,7 (ADPKD) is the most common kidney disorder indicating a genic influence on the ADPKD pheno- with a Mendelian inheritance pattern, with a prev- type. Second, the position of the PKD1 mutation is alence ranging from 1/400 to 1/1000 worldwide.1 associated with the age at ESRD onset,8 suggesting ADPKD shows both locus and allelic heterogene- an allelic influence on ADPKD phenotype. How- ity. Two causative genes—PKD1, located at ever, these observations were made .10 years ago, 16p13.3,2 and PKD2, located at 4q213—have when mutational analysis of the PKD1 and PKD2 been identified, and the ADPKD mutation data- genes (particularly of the nonunique portion of the base (http://pkdb.mayo.edu/) describes .1000 PKD1 gene2,9) was substantially less comprehensive pathogenic mutations (929 in PKD1 and 167 in PKD2 as of June 5, 2012), not including our most recent data.4 Received July 5, 2012. Accepted January 7, 2013. ADPKD also shows high phenotypic variability, Published online ahead of print. Publication date available at as exemplified by the wide variation in the age at www.jasn.org. 5 fi onset of ESRD, which is de ned as the requirement Correspondence: Dr. Claude Férec, INSERM U1078 and EFS- of dialysis or transplantation. Genotype-phenotype Bretagne, 46 rue Félix Le Dantec, 29218 Brest, France. Email: correlation studies underscore two major issues. [email protected] First, on average, ESRD occurs 20 years earlier in Copyright © 2013 by the American Society of Nephrology 1006 ISSN : 1046-6673/2406-1006 JAmSocNephrol24: 1006–1013, 2013 www.jasn.org CLINICAL RESEARCH Table 1. Patient characteristics Characteristic PKD1 Mutation Carriers PKD2 Mutation Carriers Mutation-Negative Patients Total Patients (pedigrees), n (n) 571 (392) 133 (95) 37 (32) 741 (519) Mean age (yr) 51.96 58.91 56.01 53.4 Sex (n) Male 254 50 21 325 Female 317 83 16 416 High BP Present, n (%) 474 (83) 107 (80.4) 31 (83.7) 612 Age at diagnosis (yr) 38.6 48.6 42.2 40.6 Absent (n) 92 26 6 124 Unknown (n)5005 CKD stage according to estimated GFR (MDRD formula) (n) I 74 21 4 90 (13.4) II 74 31 3 108 (14.6) III 91 38 8 137 (18.5) IV 61 12 4 77 (10.4) V Total 271 31 18 320 (43.2) Requiring dialysis (n) 51 15 4 70 (9.4) With kidney transplant (n) 192 11 7 210 (28.3) Unless otherwise noted, values in parentheses are percentages of patients. MDRD, Modification of Diet in Renal Disease. and sophisticated than it is currently,4,10 the methods for pre- Table 2. Distribution of pathogenic PKD1 and PKD2 dicting the potential pathogenicity of missense mutations mutations were in their infancy, and the studied patient cohorts were Gene/Mutation Type Pedigrees, n (%) fi relatively small. To con rm (or refute) these earlier observa- PKD1 392 tions, we performed a genotype and phenotype correlation Truncating mutations study using the Genkyst cohort, which comprises patients Total 255 (65.1) with ADPKD recruited from all private and public nephrol- Frameshift 130 (33.2) ogy centers in the Brittany region, namely, the western part of Nonsense 90 (22.9) France. Splice 32 (8.2) Large rearrangements 3 (0.8) Nontruncating mutations RESULTS Total 137 (34.9) Missense 110 (28) In-frame deletions or insertions 27 (6.9) Description of the Cohort and Distribution of the PKD1 PKD2 95 and PKD2 Mutations Truncating mutations This study included all 741 patients with ADPKD and Total 89 (93.7) molecular genetic analytic data (416 female and 325 male Frameshift 13 (13.7) patients; 519 pedigrees) registered in Genkyst between early Nonsense 41 (43.1) 2009 and July 2012. The mean age 6 SD at inclusion was Splice 20 (21.1) 53.4614.8 years (range, 5.45–89.5 years). Pathogenic muta- Large rearrangements 15 (15.8) tions in the PKD1 and PKD2 genes were found in 392 (75.5%) Nontruncating mutations 6 (6.3) and 95 (18.3%) of the 519 pedigrees, respectively (Table 1). No Total (all mutation positive pedigrees) 487 mutation was identified in the remaining 32 pedigrees (6.2%); the overall detection rate was thus 93.8%. The phenotypic characteristics of each patient group, including age, sex, BP different mutations were found in the 487 mutation-positive status with age at diagnosis of hypertension if available, and pedigrees (296 PKD1 mutations in 392 pedigrees and 46 PKD2 CKD stage in terms of estimated GFR (calculated using the mutations in 95 pedigrees). Approximately two thirds of the Modification of Diet in Renal Disease formula), are provided 342 PKD1 mutation–positive pedigrees and almost 95% of the in Table 1. 95 PKD2 mutation–positive pedigrees carry truncating muta- A large number of the pathogenic mutations in the current tions (i.e., nonsense mutations, frameshift mutations, splicing study were confined to single pedigrees. Thus, a total of 342 mutations, and large rearrangements) (Table 2). J Am Soc Nephrol 24: 1006–1013, 2013 PKD1 Mutation and Renal Outcome 1007 CLINICAL RESEARCH www.jasn.org Genotype and Phenotype Correlations of the mutation and renal survival. Tothis end, we studied renal Sex Influence survival in two main categories of PKD1 mutations, defined by Using the Kaplan-Meier model, we found that male PKD1 their truncating effect on polycystin 1. As shown in Figure 1A, mutation carriers presented with a poorer renal survival the median age at ESRD onset in the truncating mutation than female ones (median age at ESRD onset, 56.1 years for group (i.e., frameshift, nonsense, splice mutations, and large male patients versus 59.5 years for female patients; P,0.04). rearrangements) was 55.6 years (95% CI, 53.6–57.7 years), This result was confirmed using Cox multivariate analysis and mutations with no truncating effect (i.e., in-frame muta- (P=0.03) (Table 3). However, we did not find any sex influence tions and missense events) were associated with a 12-year de- in the PKD2 mutation carriers. When the two datasets were lay in ESRD onset (median age, 67.9 years [95% CI, 62.4–73.4 combined, only a borderline significance was observed; the years]) (P,0.0001). This difference was also re flected by the median age at ESRD onset was 62.8 years for male patients proportion of truncating mutations in four groups of patients, versus 65.4 years for female patients (P=0.05). corresponding to the quartile of renal survival in patients with PKD1 (i.e.,quartile1,ESRDbefore50.5years;quartile2, Gene Influence ESRD between 50.5 and 58.2 years; quartile 3, ESRD between PKD1 mutation carriers had significantly poorer renal prognosis 58.2 and 68.4 years; and quartile 4, patients .68.4 years with- than their PKD2 counterparts, with respective median ages at out ESRD). In the mildest phenotype group (i.e.,quartile4), ESRD onset of 58.1 (95% confidence interval [CI], 56.5–59.9) the proportion of truncating mutations (46.6%) was signifi- and 79.7 (95% CI, 76.8–82.6) years (P,0.001). The mean age at cantly lower than in each of the other three quartiles (quartile diagnosis of hypertension was 10 years earlier for PKD1 muta- 1, 83.3%; quartile 2, 78.9%; and quartile 3, 74%; P,0.05) tion carriers (n=315; 38.6611.3 years) than for PKD2 mutation (Figure 2A). Moreover, we assessed the robustness of our sur- carriers (n=77; 48.6611.5 years) (P,0.001) (Table 1). vival analysis using a Cox multivariate model, taking into ac- count age and sex. We found no effect of BP status, smoking, Allelic Influence of the PKD1 Gene hematuria, or mutation position on renal survival in the uni- To address the issue of allelic influence on phenotype in variate analysis (Table 3); therefore, these variables were not ADPKD, we first investigated the relationship between the type entered into the multivariate analysis.
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