A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes.

Ariza, M.J.; Álvarez, Victoria; Marín, Rafael; Aguado, S; López‐Larrea, Carlos; Alvarez, J; Menéndez, M J; Coto, Eliécer

doi:10.1136/jmg.34.7.587

Cited by 63 publications

(39 citation statements)

References 15 publications

(12 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Linkage Analysis-Two families, one Italian and one Spanish (F431 and F432) have been previously described (3,23,24), Four other families were studied: TOR1, a three-generation pedigree with 42 members of whom 26 were affected; TOR2, a two-generation pedigree with 8 members of whom 4 are affected 3 ; and Singa 1, a two-generation pedigree with 5 members of whom 4 are affected, and Bulga 1, a 3-generation pedigree with 9 members of whom 5 are affected (24).…”

Section: Methodsmentioning

confidence: 99%

Identification of PKDL, a Novel Polycystic Kidney Disease 2-Like Gene Whose Murine Homologue Is Deleted in Mice with Kidney and Retinal Defects

Nomura

Turco

Pei

et al. 1998

Journal of Biological Chemistry

151

105

View full text Add to dashboard Cite

Polycystin-1 and polycystin-2 are the products of PKD1 and PKD2, genes that are mutated in most cases of autosomal dominant polycystic kidney disease. Polycystin-2 shares ϳ46% homology with pore-forming domains of a number of cation channels. It has been suggested that polycystin-2 may function as a subunit of an ion channel whose activity is regulated by polycystin-1. Here we report the identification of a human gene, PKDL, which encodes a new member of the polycystin protein family designated polycystin-L. Polycystin-L has 50% amino acid sequence identity and 71% homology to polycystin-2 and has striking sequence and structural resemblance to the pore-forming ␣1 subunits of Ca 2؉ channels, suggesting that polycystin-L may function as a subunit of an ion channel. The full-length transcript of PKDL is expressed at high levels in fetal tissues, including kidney and liver, and down-regulated in adult tissues. PKDL was assigned to 10q24 by fluorescence in situ hybridization and is linked to D10S603 by radiation hybrid mapping. There is no evidence of linkage to PKDL in six ADPKD families that are unlinked to PKD1 or PKD2. The mouse homologue of PKDL is deleted in Krd mice, a deletion mutant with defects in the kidney and eye. We propose that PKDL is an excellent candidate for as yet unmapped cystic diseases in man and animals.Polycystin-1 and polycystin-2 are the respective gene products of PKD1 and PKD2, mutations in which account for ϳ95% of cases of ADPKD.1 ADPKD affects up to 1/1,000 individuals and is associated with a 50% incidence of end-stage renal failure by the sixth decade of life (1). At least one additional gene is known to be mutated in the ADPKD population (2, 3) but has yet to be identified.Polycystin-1 encodes a 4,303-amino acid plasma membrane protein with a large extracellular N-terminal domain that contains leucine-rich repeats, a C-type lectin domain, and an LDL-A-like domain, all three of which are involved in cell-cell or cell-matrix interactions in other proteins (4 -6). These domains are followed by 16 repeats of the so-called PKD domain and by an REJ (receptor for egg jelly in sea urchin sperm)-like domain. Polycystin-1 has 7 to 11 transmembrane domains. The short cytoplasmic tail (197 amino acids) of polycystin-1 contains a coiled-coil domain, which appears to interact with other proteins containing similar structures (7,8).The predicted amino acid sequence of the PKD2 gene is homologous to the C terminus of polycystin-1 (9, 10). Polycystin-2 is a 968-amino acid protein with ϳ46% sequence similarity to each domain of the pore-forming ␣1 subunits of Ca 2ϩ and other cation channels, and like these channel subunits, it is predicted to have six transmembrane domains. Polycystin-2 has a putative Ca 2ϩ binding structure (EF-hand) in its Cterminal cytoplasmic domain. It interacts biochemically with polycystin-1 and with itself (7,8).Here we report the identification, chromosomal localization, and expression of a third gene encoding a protein of the polycystin family. The product of this gene is ...

show abstract

Section: Methodsmentioning

confidence: 99%

Identification of PKDL, a Novel Polycystic Kidney Disease 2-Like Gene Whose Murine Homologue Is Deleted in Mice with Kidney and Retinal Defects

Nomura

Turco

Pei

et al. 1998

Journal of Biological Chemistry

151

105

View full text Add to dashboard Cite

show abstract

“…Mutations in these proteins account for the vast majority of ADPKD cases (1). However, a small number of families with ADPKD have been reported to develop PKD that seems to be unlinked to either PKD1 or PKD2, leading to the controversial suggestion of the involvement of other as-yet-unknown genes (1,2). Furthermore, several other, although less frequent, hereditary cystic kidney diseases that also lead to terminal renal failure (1) occur in childhood, adolescence, or adulthood (e.g., autosomal recessive polycystic kidney disease, nephronophthisis, medullary cystic kidney disease).…”

mentioning

confidence: 99%

Missense Mutation in Sterile α Motif of Novel Protein SamCystin is Associated with Polycystic Kidney Disease in (cy/+) Rat

Brown

Bihoreau

Hoffmann

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (PKD) is the most common genetic disease that leads to kidney failure in humans. In addition to the known causative genes PKD1 and PKD2, there are mutations that result in cystic changes in the kidney, such as nephronophthisis, autosomal recessive polycystic kidney disease, or medullary cystic kidney disease. Recent efforts to improve the understanding of renal cystogenesis have been greatly enhanced by studies in rodent models of PKD. Genetic studies in the (cy/؉) rat showed that PKD spontaneously develops as a consequence of a mutation in a gene different from the rat orthologs of PKD1 and PKD2 or other genes that are known to be involved in human cystic kidney diseases. This article reports the positional cloning and mutation analysis of the rat PKD gene, which revealed a C to T transition that replaces an arginine by a tryptophan at amino acid 823 in the protein sequence. It was determined that Pkdr1 is specifically expressed in renal proximal tubules and encodes a novel protein, SamCystin, that contains ankyrin repeats and a sterile ␣ motif. The characterization of this protein, which does not share structural homologies with known polycystins, may give new insights into the pathophysiology of renal cyst development in patients.

show abstract

“…9, 10 A third, rare form has not yet been mapped. 11,12 Even though all types of ADPKD present with an identical profile of extrarenal manifestations (including liver cysts and aneurysms), PKD1 is the most severe, with a lower median survival and a higher risk of progressing to endstage renal disease. 13,14 The PKD1 gene encodes a 14 kb mRNA that is derived from 46 exons that extend over B50 kb of genomic DNA.…”

Section: Introductionmentioning

confidence: 99%

Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition

et al. 2004

View full text Add to dashboard Cite

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of epithelial cells and the influx of cyst fluid. The 14-kb mRNA of the polycystic kidney disease gene, PKD1, encodes the polycystin-1 protein, whose function remains unknown. In this study, we observed that polycystin-1 localized in epithelial cell -cell contacts of 293 cells. We found, by bromodeoxyuridine (BrdU) incorporation experiments and Western blot analysis of S-phase-specific cyclins, that the depletion of polycystin-1 led to an increased cell proliferation rate and caused a premature G1/S-phase transition. In addition, we showed that the depletion of polycystin-1 reduced the amount of p53 in 293 cells irradiated by UV light, suggesting that polycystin-1 acts as a regulator of G1 checkpoint, which controls entry into the S phase and prevents the replication of damaged DNA. Our results might provide an insight into the formation and progression of ADPKD cysts.

show abstract

A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes.

Cited by 63 publications

References 15 publications

Identification of PKDL, a Novel Polycystic Kidney Disease 2-Like Gene Whose Murine Homologue Is Deleted in Mice with Kidney and Retinal Defects

Identification of PKDL, a Novel Polycystic Kidney Disease 2-Like Gene Whose Murine Homologue Is Deleted in Mice with Kidney and Retinal Defects

Missense Mutation in Sterile α Motif of Novel Protein SamCystin is Associated with Polycystic Kidney Disease in (cy/+) Rat

Depletion of PKD1 by an antisense oligodeoxynucleotide induces premature G1/S-phase transition

Contact Info

Product

Resources

About