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• W2065928247 abstract "Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation. Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive bilateral cyst development and expansion, often resulting in end-stage renal disease (ESRD). The disease is genetically heterogeneous with two loci identified: PKD1, ∼85% of cases (16p13.3) and PKD2, ∼15% (4q21).1.European Polycystic Kidney Disease Consortium The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16.Cell. 1994; 77: 881-894Abstract Full Text PDF PubMed Scopus (705) Google Scholar, 2.Mochizuki T. Wu G. Hayashi T. et al.PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.Science. 1996; 272: 1339-1342Crossref PubMed Scopus (1102) Google Scholar, 3.Rossetti S. Consugar M.B. Chapman A.B. et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 2143-2160Crossref PubMed Scopus (298) Google Scholar The ADPKD phenotype displays marked variability4.Rossetti S. Harris P.C. Genotype–phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 1374-1380Crossref PubMed Scopus (121) Google Scholar that is greatly influenced by the gene type: PKD1 has an average age at ESRD of 54.3 years compared to 74 years for PKD2.5.Hateboer N. van Dijk M.A. Bogdanova N. et al.Comparison of phenotypes of polycystic kidney disease types 1 and 2.Lancet. 1999; 353: 103-107Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar Significant intrafamilial variability also highlights a role for the genetic background in the disease presentation.6.Paterson A.D. Magistroni R. He N. et al.Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2005; 16: 755-762Crossref PubMed Scopus (72) Google Scholar Extreme intrafamilial variability manifests in a small proportion of cases (∼1–2%) with early onset ADPKD, clinical symptoms before 15 years, and rarely results in in utero cystic enlargement more typical of autosomal recessive polycystic kidney disease.7.Kaariainen H. Polycystic kidney disease in children: a genetic and epidemiological study of 82 Finnish patients.J Med Genet. 1987; 24: 474-481Crossref PubMed Scopus (52) Google Scholar, 8.Zerres K. Rudnik-Schöneborn S. Deget F. et al.Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk.J Med Genet. 1993; 30: 583-588Crossref PubMed Google Scholar Most early onset cases have been linked to PKD1, but recently a PKD2 family with perinatal death in two severely affected infants was described.9.Bergmann C. Bruchle N.O. Frank V. et al.Perinatal deaths in a family with autosomal dominant polycystic kidney disease and a PKD2 mutation.N Engl J Med. 2008; 359: 318-319Crossref PubMed Scopus (24) Google Scholar, 10.MacDermot K.D. Saggar-Malik A.K. Economides D.L. et al.Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis for very early onset disease.J Med Genet. 1998; 35: 13-16Crossref PubMed Scopus (66) Google Scholar, 11.Michaud J. Russo P. Grignon A. et al.Autosomal dominant polycystic kidney disease in the fetus.Am J Med Genet. 1994; 51: 240-246Crossref PubMed Scopus (37) Google Scholar, 12.Peral B. Ong A.C.M. San Millán J.L. et al.A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1).Hum Mol Genet. 1996; 5: 539-542Crossref PubMed Scopus (102) Google Scholar, 13.Watnick T. Phakdeekitcharoen B. Johnson A. et al.Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease.Am J Hum Genet. 1999; 65: 1561-1571Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar As illustrated in this case, siblings of early onset cases have a significantly enhanced risk of severe disease.8.Zerres K. Rudnik-Schöneborn S. Deget F. et al.Childhood onset autosomal dominant polycystic kidney disease in sibs: clinical picture and recurrence risk.J Med Genet. 1993; 30: 583-588Crossref PubMed Google Scholar Early onset ADPKD can be caused by contiguous deletion of the adjacent PKD1 and tuberous sclerosis gene (TSC2), characterized by childhood polycystic kidney disease (PKD) with additional clinical signs of tuberous sclerosis.14.Sampson J.R. Maheshwar M.M. Aspinwall R. et al.Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene.Am J Hum Genet. 1997; 61: 843-851Abstract Full Text PDF PubMed Scopus (241) Google Scholar Another genetic factor that can modulate the disease presentation and result in marked intrafamilial variability is mosaicism.15.Connor A. Lunt P.W. Dolling C. et al.Mosaicism in autosomal dominant polycystic kidney disease revealed by genetic testing to enable living related renal transplantation.Am J Transplant. 2008; 8: 232-237PubMed Google Scholar, 16.Consugar M.B. Wong W.C. Lundquist P.A. et al.Characterization of large rearrangements associated in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome.Kidney Int. 2008; 74: 1468-1479Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Bilineal inheritance of a PKD1 and a PKD2 mutant allele can also result in a modest enhancement to the single gene phenotypes.17.Pei Y. Paterson A.D. Wang K.R. et al.Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease.Am J Hum Genet. 2001; 68: 355-363Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Comprehensive base-pair mutation screening of PKD1 and PKD2 has identified definite, truncating mutations in ∼61% of cases; a further ∼4% have larger deletion/duplication mutations.3.Rossetti S. Consugar M.B. Chapman A.B. et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 2143-2160Crossref PubMed Scopus (298) Google Scholar, 16.Consugar M.B. Wong W.C. Lundquist P.A. et al.Characterization of large rearrangements associated in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome.Kidney Int. 2008; 74: 1468-1479Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Rigorous testing of amino-acid substitutions using a Grantham matrix score,18.Grantham R. Amino acid difference formula to help explain protein evolution.Science. 1974; 185: 862-864Crossref PubMed Scopus (1539) Google Scholar plus analysis of segregation and other detected variants, has resulted in likely missense changes being defined in an additional ∼26% of cases. The molecular basis of disease in approximately 9% of ADPKD remains unclear. Genotype/phenotype studies have suggested a modest influence of mutation position in PKD1, but have not shown a difference in severity between truncating and missense changes associated with either gene, suggesting likely inactivation of these missense variants.19.Rossetti S. Burton S. Strmecki L. et al.The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease.J Am Soc Neph. 2002; 13: 1230-1237Crossref PubMed Scopus (159) Google Scholar, 20.Magistroni R. He N. Wang K. et al.Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2003; 14: 1164-1174Crossref PubMed Scopus (101) Google Scholar This contrasts with autosomal recessive polycystic kidney disease where less severe disease is associated with at least one PKHD1 missense mutation, indicating the importance of incompletely penetrant alleles.21.Bergmann C. Senderek J. Sedlacek B. et al.Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1).J Am Soc Nephrol. 2003; 14: 76-89Crossref PubMed Scopus (146) Google Scholar Evidence from animal models of ADPKD and analysis of cystic epithelia indicate that renal cysts develop from loss of functional PKD protein (polycystin) with somatic inactivation of the normal allele suggesting a two-hit mechanism.22.Qian F. Watnick T.J. Onuchic L.F. et al.The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type 1.Cell. 1996; 87: 979-987Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar, 23.Lu W. Peissel B. Babakhanlou H. et al.Perinatal lethality with kidney and pancreas defects in mice with a targeted Pkd1 mutation.Nat Genet. 1997; 17: 179-181Crossref PubMed Scopus (357) Google Scholar, 24.Wu G. D'Agati V. Cai Y. et al.Somatic inactivation of Pkd2 results in polycystic kidney disease.Cell. 1998; 93: 177-188Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar However, the dosage level of functional polycystin may also be important because mouse models expressing low levels (<20%) of correctly spliced product develop cysts but are viable as homozygotes.25.Jiang S.T. Chiou Y.Y. Wang E. et al.Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1.Am J Pathol. 2006; 168: 205-220Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 26.Lantinga-van Leeuwen I.S. Dauwerse J.G. Baelde H.J. et al.Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease.Hum Mol Genet. 2004; 13: 3069-3077Crossref PubMed Scopus (231) Google Scholar No corresponding human hypomorphic or incompletely penetrant PKD1 or PKD2 alleles have been described. Here we describe a number of unusual families with atypical presentations of PKD that suggest a role for incompletely penetrant PKD1 alleles in causing and modulating cystic disease. Analysis of over 100 apparent ADPKD families, including ones with unusually severe and mild disease and marked intrafamilial variability, identified three that did not fit the normal ADPKD paradigm of a single dominantly inherited mutation. The proband (II2) had bilaterally enlarged kidneys and ESRD at age 75 years whereas a brother (II3) required a renal transplant at 62 years (Figure 1a). The appearance of the kidneys in the two siblings was similar and atypical for ADPKD in that multiple, relatively uniformly sized cysts were found (Figure 1b), compared to the marked heterogeneity in cyst size typical of this disorder. Mild dilatation of the calyces was also seen in II2 (Figure 1b). Unusually for older ADPKD patients, neither had liver cysts. Multiple small cortical renal cysts were identified in the father at autopsy at 79 years. The mother died at 83 from a stroke with PKD unknown. The proband's children (III1, III2, and III4) each had a small number of renal cysts (see Figure 1a and b) without renal enlargement, in their 40s. The granddaughter (IV1) had a single cyst at 28 years, whereas another brother (II5) had five cysts at 76 years (Figure 1a and b). Although this cyst number was suggestive of a positive diagnosis in these individuals with the family history of ADPKD, the severity of disease was very different between generations. Mutation analysis by direct sequencing of PKD1 and PKD2 exons revealed homozygosity for 13 PKD1 intragenic polymorphisms. Subsequently, the parents (I1 and I2) were found to be first cousins. In addition, the novel PKD1 substitution 9829C → T, resulting in R3277C (Figure 1c), was found homozygous in II2 and II3 and heterozygous in other family members with renal cysts (Figure 1a). No large deletion mutation was detected in II2 or II3 using a multiple ligation-dependent probe amplification assay for the PKD1 and PKD2 genes, and no PKHD1 mutations were detected. R3277C is at a highly conserved site in polycystin-1 (PC1), completely conserved to fish (Grantham variation, GV=0) and is a highly nonconservative substitution (Grantham distance, GD=180) (Figure 1d).3.Rossetti S. Consugar M.B. Chapman A.B. et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 2143-2160Crossref PubMed Scopus (298) Google Scholar, 18.Grantham R. Amino acid difference formula to help explain protein evolution.Science. 1974; 185: 862-864Crossref PubMed Scopus (1539) Google Scholar The missense change is located in the first intracellular loop of PC1, close to transmembrane region 2, and is highly conserved in other PC1-like proteins (Figure 1d). To more rigorously test the significance of this substitution, three tools to predict pathological mutations were tested. These tools (SIFT, PolyPhen, and AlignGVGD) were used utilizing default conditions and/or by using an alignment of PC1 orthologues (see Materials and Methods, Table S1, and Supplementary Results for details). Evaluation of R3277C showed that it was predicted to be a strong pathogenic mutation in each case (Table 1). Overall, this family suggested that R3277C was an incompletely penetrant mutant allele that resulted in occasional cyst development in heterozygotes and more severe PKD in homozygosity.Table 1Scoring of PC1 variants for likely pathogenicitySIFTaDefault alignment.SIFTbPC1 orthologue alignment.PolyPhenaDefault alignment.AlignGVGDbPC1 orthologue alignment.ConsensusVariantMGVSMGVSMGVSMGVSMGR2765CC0.01C0.01B2.17CC35B/CR3105WB0B0B2.60CC35BN3188SC0.03B0C1.84CC45CR3277CB0B0B2.65BC65BB, highly likely; C, likely; MG, mutation group; PC1; polycystin-1; VS, variant score.a Default alignment.b PC1 orthologue alignment. Open table in a new tab B, highly likely; C, likely; MG, mutation group; PC1; polycystin-1; VS, variant score. A second consanguineous family of Pakistani origin presented a pattern typical of dominant inheritance (Figure 2a). The father (I1) had bilateral PKD, but as above, the finding of multiple small cysts (4–7 mm) was not completely characteristic of ADPKD, with clubbing of the calyces also detected. II2 had PKD diagnosed at 22 weeks gestation with large hyperechogenic kidneys and at 14 years had slightly enlarged kidneys with multiple (10–12 mm) cysts scattered throughout the parenchyma. No liver cysts were detected. Glomerular filtration rate at 15.5 years was 67 ml/min per 1.73 m2. Her sister (II3) had bilateral renal cysts detected at 9 years and at 15 years had a normal glomerular filtration rate (86 ml/min per 1.73 m2) with several cortical cysts, including ones of 12 and 17 mm, but no liver cysts. An earlier pregnancy that resulted in a stillbirth (II1) was found to have bilateral PKD but no biliary dysgenesis (typical of autosomal recessive polycystic kidney disease) at autopsy. Haplotype analysis with five markers flanking PKD1 (see Materials and Methods for details) indicated homozygosity of ∼450 kb around PKD1 in I1, II2, and II3 with a similar single copy of the same haplotype in the mother (I2) and unaffected children (II4 and II5). Sequence analysis of PKD1 and PKD2 in I1 showed homozygosity of four intragenic PKD1 single nucleotide polymorphisms. A novel substitution in PKD1, 9563A → G; N3188S, was homozygous in the affected cases and heterozygous in the others (Figure 2a and b). This residue is completely conserved to fish (GV=0), is a moderately conservative change (GD=46), and highly conserved in other PC1-like proteins (Figure 2c). It lies in the PLAT domain27.Bateman A. Sandford R. The PLAT domain: a new piece in the PKD1 puzzle.Curr Biol. 1999; 9: R588-R590Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar but is not at a highly conserved position in the domain. Analysis with the prediction tools indicated that it was most likely a pathogenic change (Table 1). Deletion of N318828.Rossetti S. Chauveau D. Kubly V. et al.Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype.Lancet. 2003; 361: 2196-2201Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar as a mutation has been described. This substitution is close to the junction with IVS27, but reverse transcription–PCR analysis of this change did not reveal abnormal splicing. A possible large deletion mutation causing hemizygosity across the PKD1 region was excluded by multiple ligation-dependent probe amplification analysis of PKD1, and no PKHD1 mutations were detected. The proband (II5) in M390 (Figure 3a) was diagnosed by excretory urography at 11 years with medullary sponge kidney and bilateral renal cysts consistent with PKD, following multiple urinary tract infections. Images at 32 years showed multiple renal cysts and three liver cysts (Figure 3b). The kidneys were not particularly enlarged (RK, 12.2 cm; LK, 12.1 cm at 22 years). Cortical scars consistent with reflux nephropathy were also seen, with a history of multiple urinary tract infections during childhood. The sister (II2) had one 2.2 cm cyst (42 years; Figure 3c), while II3 had one kidney cyst and liver cyst (2.5 cm) but the parents were apparently unaffected. Mutation screening of II5 revealed two PKD1 missense variants, 9313C → T; R3105W, and 8293C → T; R2765C (Figure 3d). R3105W is a novel, nonconservative change (GD=101) at a well-conserved site in orthologues (GV=26) and homologues (Figure 3e). R2765C is a nonconservative change (GD=180) at a conserved site of basic residues (GV=29), but is not part of a conserved domain (Figure 3f). Formal analysis of these variants predicted that both are likely pathogenic changes (Table 1). Various other members of the family had one or other of the variants but not both (Figure 3a), including the sisters with single renal cysts. The pattern of inheritance suggested that both incompletely penetrant variants are required for polycystic kidney disease development and that a single variant can be associated with rare cyst development. We reasoned that the identified incompletely penetrant PKD1 alleles in trans with an inactivating allele may cause early onset ADPKD; hence, we screened families with an in utero presentation of PKD and a family history of ADPKD. In P438; III1 (Figure 4a), PKD was diagnosed in utero with bilateral, substantially enlarged hyperechogenic kidneys (RK=9 cm; LK=10 cm) at 7 days, and hypertension diagnosed at 5 months. The kidneys had no corticomedullary differentiation and multiple small cysts, with an SC=1.7 mg/100 ml at 17 years. The father was diagnosed with ADPKD at 15 years and had an SC=1.5 mg/100 ml at 44 years. The grandmother had ESRD at 43 years. Screening the ADPKD genes showed PKD1: Q2158X as the likely disease-causing mutation, but that the in utero case (III1) also had the R3277C variant, presumably inherited from the apparently unaffected mother. In P117, one (III2) of a pair of dizygotic twins was diagnosed in utero at 31 weeks with enlarged bilaterally cystic kidneys that were at the 95th percentile (8 cm) at 10 months.12.Peral B. Ong A.C.M. San Millán J.L. et al.A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1).Hum Mol Genet. 1996; 5: 539-542Crossref PubMed Scopus (102) Google Scholar III2 was hypertensive since age 2 years and had multiple bilateral cysts and a glomerular filtration rate of 89 ml/min per 1.73 m2 at 15 years. Her twin brother III1 had more typical ADPKD with two cysts in the left kidney and one in the right at 10 years. Their father had multiple renal cysts, but normal renal function at 28 years (Figure 4b). In P118, III1 died perinatally of pulmonary hypoplasia with massively enlarged cystic kidneys.19.Rossetti S. Burton S. Strmecki L. et al.The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease.J Am Soc Neph. 2002; 13: 1230-1237Crossref PubMed Scopus (159) Google Scholar The mother II2 had multiple cysts and enlarged kidneys at 35 years, typical of ADPKD, and five cysts were found (up to 5 cm in diameter) in I1. In both families the nonconservative variant R2765C was found inherited in trans with a truncating mutation (P117; Y3819X: P118; 7915dup20)12.Peral B. Ong A.C.M. San Millán J.L. et al.A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1).Hum Mol Genet. 1996; 5: 539-542Crossref PubMed Scopus (102) Google Scholar, 29.Rossetti S. Strmecki L. Gamble V. et al.Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications.Am J Hum Genet. 2001; 68: 46-63Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar in the severely affected cases (Figure 4b and c). Cases with just the R2765C variant did not have renal cysts by ultrasound examination. Unlike the other variants described here that have only been seen in these families, R2765C is a more common variant found on ∼1% of normal alleles and described in three studies.30ADPKD Mutation Database (PKDB) In, http://pkdb.mayo.edu 2008.Google Scholar In two other families analyzed with typical ADPKD, R2765C segregated in cis with the likely pathogenic mutation, whereas segregation data were not available in three other families with that variant. We have analyzed three families with ADPKD-like disease that are not explained by dominant inheritance of a single mutation to PKD1 or PKD2. Several pieces of data indicate a novel mechanism, including the pattern of inheritance and haplotypes, unusual distribution of cysts, sequence analysis of PKD1 and PKD2 and scoring of variants, and exclusion of other causes of disease. Consistent with the ADPKD-like phenotype, we provide strong data that atypical PKD1 alleles underlie the disease etiology in these families. The inheritance pattern in M34 is consistent with autosomal dominance but it exhibits extreme differences in severity between generations. Although intrafamilial variability is seen in ADPKD,31.Geberth S. Ritz E. Zeier M. et al.Anticipation of age at renal death in autosomal dominant polycystic kidney disease (ADPKD)?.Nephrol Dial Transplant. 1995; 10: 1603-1606PubMed Google Scholar it does not usually range from ESRD in 60s to the minimal cyst development in the 40s, as seen here. The homozygosity of a highly conserved PKD1 mutation in the cases with ESRD, plus heterozygosity in those with a few cysts, suggested the involvement of an incompletely penetrant allele. In P192, the inheritance pattern is apparently dominant, but haplotype and sequence data again showed a PKD1 homozygous mutation associated with moderate to severe cystic disease. In the final family, M390, inheritance appears recessive and only the compound heterozygote with two highly conserved PKD1 variants has significant cystic disease. PKD1 is highly polymorphic with ∼10 neutral variants found per patient from exonic sequencing.3.Rossetti S. Consugar M.B. Chapman A.B. et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 2143-2160Crossref PubMed Scopus (298) Google Scholar However, the majority are known variants, whereas most novel neutral changes are at poorly conserved sites or are conservative substitutions (Table S1). The four variants highlighted in this study bear all the characteristics of pathogenic missense changes. This is reflected in both the Grantham matrix score and the more formal analysis of likely pathogenicity that rates them as ‘highly likely’ (Mutation Group B) or ‘likely’ (Mutation Group C)3.Rossetti S. Consugar M.B. Chapman A.B. et al.Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2007; 18: 2143-2160Crossref PubMed Scopus (298) Google Scholar mutations. However, it is clear from the heterozygous phenotypes that none are fully penetrant mutations as at the most extreme they are only associated with a handful of renal cysts by middle age. We propose that these partially penetrant alleles, associated with a protein with some residual function (similar to some PKHD1 missense changes) are functionally analogous to described murine Pkd1 hypomorphic alleles.25.Jiang S.T. Chiou Y.Y. Wang E. et al.Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1.Am J Pathol. 2006; 168: 205-220Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 26.Lantinga-van Leeuwen I.S. Dauwerse J.G. Baelde H.J. et al.Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease.Hum Mol Genet. 2004; 13: 3069-3077Crossref PubMed Scopus (231) Google Scholar To prove the significance of these variants, a functional test for PC1 is required, but unfortunately no such assay yet exists. In parts of the protein (the REJ and GPS regions), the significance of missense changes has been assessed by their ability to prevent cleavage at the GPS site.32.Qian F. Boletta A. Bhunia A.K. et al.Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations.Proc Natl Acad Sci USA. 2002; 99: 16981-16986Crossref PubMed Scopus (221) Google Scholar However, the variants described here in the transmembrane region are unlikely to influence cleavage. Furthermore, as we propose that these are incompletely penetrant alleles, obtaining clear results from any functional assay may be difficult. Mimicking these changes in a mouse knock-in model (a time-consuming process) may be the only clear way to prove their significance. Recently, a homozygous PKD2 variant, F482C, that alters polycystin-2 channel activity, was suggested to modulate disease due to a PKD1 splicing mutation.33.Dedoussis G.V. Luo Y. Starremans P. et al.Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease.Eur J Clin Invest. 2008; 38: 180-190Crossref PubMed Scopus (20) Google Scholar Syndromic forms of PKD also exhibit genetic complexity, including oligogenic inheritance and phenotypic modulation by hypomorphic mutations.34.Badano J.L. Kim J.C. Hoskins B.E. et al.Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet–Biedl patients with two mutations at a second BBS locus.Hum Mol Genet. 2003; 12: 1651-1659Crossref PubMed Scopus (151) Google Scholar, 35.Hoefele J. Wolf M.T. O'Toole J.F. et al.Evidence of oligogenic inheritance in nephronophthisis.J Am Soc Nephrol. 2007; 18: 2789-2795Crossref PubMed Scopus (105) Google Scholar, 36.Leitch C.C. Zaghloul N.A. Davis E.E. et al.Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet–Biedl syndrome.Nat Genet. 2008; 40: 443-448Crossref PubMed Scopus (292) Google Scholar We propose here that specific PKD1 variants can be important" @default.
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• W2065928247 title "Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease" @default.
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