A Spectrum of Mutations in the Second Gene for Autosomal Dominant Polycystic Kidney Disease (PKD2)

Veldhuisen, Barbera; Saris, Jasper J.; Haij, Simone de; Hayashi, Tomohito; Reynolds, David M.; Mochizuki, Toshio; Elles, Rob; Fossdal, Ragnheiður; Bogdanova, Nadja; Dijk, Marjan A. van; Coto, Eliécer; Ravine, David; Nørby, Søren; Verellen‐Dumoulin, Christine; Breuning, M. H.; Somlo, Stefan; Peters, Dorien J.M.

doi:10.1086/515497

Cited by 95 publications

(56 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, considerable renal disease variability (age range of onset of ESRD, 40 to 88 yr) was also evident between individual patients. described (17)(18)(19)(20)(21)(22)(23)(24)(25), and the remaining mutations from 21 families are reported here for the first time. The diagnosis of ADPKD in the patients and at-risk individuals from each study family was established using well-established ultrasound-based criteria (26).…”

Section: Study Patientsmentioning

confidence: 99%

“…DNA isolation and mutation screening methods have been previously detailed (17)(18)(19)(20)(21)(22)(23)(24). Single-stranded conformational polymorphism (SSCP), heteroduplex analysis (HA), or direct sequencing was employed to screen all 15 exons and their flanking intronic sequences of PKD2 (28) for PKD2 mutations in one definitively affected individual from each study family.…”

Section: Pkd2 Mutational Analysesmentioning

confidence: 99%

See 1 more Smart Citation

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Magistroni

He²,

Wang³

et al. 2003

Journal of the American Society of Nephrology

124

View full text Add to dashboard Cite

Abstract. Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance Յ 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P Ͻ 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.

show abstract

Section: Study Patientsmentioning

confidence: 99%

Section: Pkd2 Mutational Analysesmentioning

confidence: 99%

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Magistroni

He²,

Wang³

et al. 2003

Journal of the American Society of Nephrology

124

View full text Add to dashboard Cite

show abstract

“…17 A total of 270 different PKD1 and 73 PKD2 mutations are described in the Human Gene Mutation Database (HGMD), illustrating the high level of allelic heterogeneity; most mutations are unique to a single family. [17][18][19] The majority of changes are predicted to truncate the proteins, although a significant number of missense changes have been described. …”

mentioning

confidence: 99%

Comprehensive Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease

Rossetti

Consugar

Chapman

et al. 2007

Journal of the American Society of Nephrology

372

401

View full text Add to dashboard Cite

Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available. 18: 214318: -216018: , 200718: . doi: 10.1681 Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, with an incidence of 1 in 400 to 1000 (accounting for approximately 5% of ESRD), and is characterized by the development and progressive enlargement of cysts in the kidney. ADPKD is genetically heterogeneous, with two genes identified: PKD1 (16p13.3) and PKD2 (4q21). [1][2][3][4] In linkagecharacterized populations, PKD1 accounts for approximately 85% of cases and PKD2 accounts for most of the remainder, 5,6 but further heterogeneity is possible. 7 PKD1 has an average age at ESRD of 54.3 yr, compared with 74.0 yr for PKD2. 8 PKD1 and PKD2 encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a TRP channel that may be involved in regulating intracellular Ca 2ϩ . 9,10 PC1 and PC2 interact and, similar to other cystogenic proteins, have been localized to primary cilia. 11,12 This complex may act as a flow-dependent mechanosensor that regulates the differentiated state of tubular epithelial cells. 13 The diagnosis of ADPKD is typically determined by renal imaging wit...

show abstract

“…Although the germline mutations at PKD2 14 and PKD1 15 are probably inactivating, controversy exists over the additional steps necessary for focal cyst development. Evidence of loss of heterozygosity in individual PKD1 renal 16,17 and liver cysts 18 and recent data from targeted disruption of the mouse Pkd2 gene 19 favor a two-hit mechanism involving somatic inactivation of the normal allele.…”

mentioning

confidence: 99%

Coordinate Expression of the Autosomal Dominant Polycystic Kidney Disease Proteins, Polycystin-2 And Polycystin-1, in Normal and Cystic Tissue

Ong

Ward

Butler

et al. 1999

The American Journal of Pathology

176

151

View full text Add to dashboard Cite

A second gene for autosomal dominant polycystic kidney disease (ADPKD) , PKD2, has been recently identified. Using antisera raised to the human PKD2 protein , polycystin-2 , we describe for the first time its distribution in human fetal tissues , as well as its expression in adult kidney and polycystic PKD2 tissues. Its expression pattern is correlated with that of the PKD1 protein , polycystin-1. In normal kidney, expression of polycystin-2 strikingly parallels that of polycystin-1 , with prominent expression by maturing proximal and distal tubules during development, but with a more pronounced distal pattern in adult life. In nonrenal tissues expression of both polycystin molecules is identical and especially notable in the developing epithelial structures of the pancreas, liver , lung , bowel , brain , reproductive organs, placenta , and thymus. Of interest , nonepithelial cell types such as vascular smooth muscle , skeletal muscle , myocardial cells , and neurons also express both proteins. In PKD2 cystic kidney and liver , we find polycystin-2 expression in the majority of cysts, although a significant minority are negative , a pattern mirrored by the PKD1 protein. The continued expression of polycystin-2 in PKD2 cysts is similar to that seen by polycystin-1 in PKD1 cysts , but contrasts with the reported absence of polycystin-2 expression in the renal cysts of Pkd2؉/؊ mice. These results suggest that if a two-hit mechanism is required for cyst formation in PKD2 there is a high rate of somatic missense mutation. The coordinate presence or loss of both polycystin molecules in the same cysts supports previous experimental evidence that hetero- Renal cysts are the primary cause of morbidity in autosomal dominant polycystic kidney disease (ADPKD) but it is evident that the disease phenotype extends beyond the kidney. Cysts are commonly found in the liver and pancreas and have been reported in testis, spleen, ovary, uterus, esophagus, and brain. Moreover, abnormalities suggestive of a generalized disorder of connective tissue, including cardiac valvular abnormalities (especially mitral valve prolapse), intracranial berry aneurysms, colonic diverticulae, inguinal hernia, and a family with Marfanoid habitus, have been described. 1,2 Mutations in two genes, PKD1 and PKD2, account for the vast majority of patients with ADPKD. The identification of these genes 3,4 has thus provided a new opportunity to study the pathophysiology of ADPKD. The predicted proteins appear quite different in structure (the PKD1 protein, polycystin-1, is ϳ4 times larger than its counterpart, polycystin-2 4,5 ). Nonetheless, they share a significant region of homology in their transmembrane regions, an area also similar to a family of voltage-gated calcium/sodium channels. 4,6 Recent evidence indicates that the ADPKD proteins may interact in experimental systems. 7,8 PKD2 is less prevalent than PKD1, accounting for ϳ15% of ADPKD cases, 9,10 but preliminary evidence suggests they share the same spectrum of extrarenal manifestations. In one st...

show abstract

A Spectrum of Mutations in the Second Gene for Autosomal Dominant Polycystic Kidney Disease (PKD2)

Cited by 95 publications

References 44 publications

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Comprehensive Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease

Coordinate Expression of the Autosomal Dominant Polycystic Kidney Disease Proteins, Polycystin-2 And Polycystin-1, in Normal and Cystic Tissue

Contact Info

Product

Resources

About