Autosomal dominant polycystic kidney disease: evidence for the existence of a third locus in a Portuguese family

Almeida, Silvana; Almeida, Edgar; Peters, Dorien J.M.; Pinto, J. R.; Távora, Isabel; Lavinha, João; Breuning, Martijn H.; Prata, MJ

doi:10.1007/bf00214191

Cited by 105 publications

(44 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This direct interaction is consistent with the clinical observation that patients with mutations of either PKD1 or PKD2 develop an identical phenotype of renal and extrarenal disease (although a milder form of the disease results from mutations of PKD2) (20,21). Evidence for the involvement of a third genetic locus in PKD includes the existence of diseases that resemble PKD and for which genetic linkage to PKD1 or PKD2 has been excluded (22)(23)(24)(25).…”

Section: Discussionsupporting

confidence: 84%

Genomic Organization and Functional Analysis of Murine PKD2L1

Murakami

Ohba

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mutations in genes that encode polycystins 1 or 2 cause polycystic kidney disease (PKD). Here, we report the genomic organization and functional expression of murine orthologue of human polycystin-2L1 (PKD2L1). The murine PKD2L1 gene comprises 15 exons in chromosome 19C3. Coexpression of PKD2L1 together with polycystin-1 (PKD1) resulted in the expression of PKD2L1 channels on the cell surface, whereas PKD2L1 expressed alone was retained within the endoplasmic reticulum (ER). This suggested that interaction between PKD1 and PKD2L1 is essential for PKD2L1 trafficking and channel formation. Deletion analysis at the cytoplasmic tail of PKD2L1 revealed that the coiled-coil domain was important for trafficking by PKD1. Mutagenesis within two newly identified ER retention signal-like amino acid sequences caused PKD2L1 to be expressed at the cell surface. This indicated that the coiled-coil domain was responsible for retaining PKD2L1 within the ER. Functional analysis of murine PKD2L1 expressed in HEK 293 cells was undertaken using calcium imaging. Coexpression of PKD1 and PKD2L1 resulted in the formation of functional cation channels that were opened by hypo-osmotic stimulation, whereas neither molecule formed functional channels when expressed alone. We conclude that PKD2L1 forms functional cation channels on the plasma membrane by interacting with PKD1. These findings raise the possibility that PKD2L1 represents the third genetic locus that is responsible for PKD.

show abstract

Section: Discussionsupporting

confidence: 84%

Genomic Organization and Functional Analysis of Murine PKD2L1

Murakami

Ohba

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Two of these, PKD1 and PKD2, have been cloned and sequenced (2)(3)(4)(5). Families with ADPKD unlinked to PKD1 or PKD2 have been identified, so at least 1 more locus must exist (6)(7)(8)(9). Both PKD1 and PKD2 code for novel molecules whose biochemical functions are unknown.…”

Section: Introductionmentioning

confidence: 99%

Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins

Huan¹,

Adelsberg²

1999

J. Clin. Invest.

219

150

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is a common human genetic disease characterized by cyst formation in kidney tubules and other ductular epithelia. Cells lining the cysts have abnormalities in cell proliferation and cell polarity. The majority of ADPKD cases are caused by mutations in the PKD1 gene, which codes for polycystin-1, a large integral membrane protein of unknown function that is expressed on the plasma membrane of renal tubular epithelial cells in fetal kidneys. Because signaling from cell-cell and cell-matrix adhesion complexes regulates cell proliferation and polarity, we speculated that polycystin-1 might interact with these complexes. We show here that polycystin-1 colocalized with the cell adhesion molecules E-cadherin and α-, β-, and γ-catenin. Polycystin-1 coprecipitated with these proteins and comigrated with them on sucrose density gradients, but it did not colocalize, coprecipitate, or comigrate with focal adhesion kinase, a component of the focal adhesion. We conclude that polycystin-1 is in a complex containing E-cadherin and α-, β-, and γ-catenin. These observations raise the question of whether the defects in cell proliferation and cell polarity observed in ADPKD are mediated by E-cadherin or the catenins.

show abstract

“…1 At least three different genes are involved in this disease: polycystic kidney disease 1 (PKD1), 2 localised at 16p13.3; PKD2 localised at 4q13-23 3 and a third locus still unmapped. 4,5 To date, several mutations have been described in the PKD1 and PKD2 genes, most of them are expected to produce truncated proteins (http://www.uwcm.ac.uk/uwcm/mg). These truncating mutations suggest that ADPKD is caused by inadequate levels of polycystin (ie haploinsufficiency), by a model of dominant/negative function, in which a mutated form of polycystin would inactivate the normal polycystin produced by the normal allele, or by a cellular recessive mechanism.…”

Section: Introductionmentioning

confidence: 99%

Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients

et al. 2000

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest genetic diseases in man, affecting 1:1000 individuals in the Caucasian population. It is caused by mutations in the PKD1 or PKD2 genes. Recently, controversial data regarding the mutational mechanism underlying cyst initiation have been reported: genetic analyses have shown that second somatic mutations may lead to cyst formation (detected as microsatellite loss of heterozygosity, LOH, and point mutations), but immunohistochemical studies show strong immunoreactivity for polycystin in some cysts. In order to further characterise this matter we have analysed 211 cysts from seven different patients for LOH, we have detected a 13.3% LOH for PKD1. This loss was specific to PKD1 as no LOH was detected when other chromosomal regions were studied. Whenever linkage analysis has been possible, it has been proved that the lost allele corresponded to the wild-type. Our data supports previous results in the two-hit theory for ADPKD due to the large number of cysts studied. ADPKD would occur through a recessive cellular mechanism. The probability of cyst development would depend on the probability of mutation in the second allele. The different phenotypical expression of the same mutation reported in ADPKD could be due to the different tendency of inactivation in the second allele in each individual.

show abstract

Autosomal dominant polycystic kidney disease: evidence for the existence of a third locus in a Portuguese family

Cited by 105 publications

References 22 publications

Genomic Organization and Functional Analysis of Murine PKD2L1

Genomic Organization and Functional Analysis of Murine PKD2L1

Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins

Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients

Contact Info

Product

Resources

About