An efficient linkage analysis strategy for autosomal dominant polycystic kidney disease

Onoe, Tamehito; Konoshita, Tadashi; Miyagi, Kyoko; Yamada, Kazunori; Mutoh, H.; Koni, Ichiro; Nomura, Hideki

doi:10.5414/cnp59406

Cited by 4 publications

(4 citation statements)

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“…Genetic DNAs were extracted from peripheral blood leukocytes. AmpliTaq gold DNA polymerase (Applied Biosystems, Foster City, CA, USA) and a universal touchdown thermal cycling program with GeneAtlas PC 320 (Astec, Fukuoka, Japan) were applied as described [ 11 ]. For some GC-rich regions, LATaq (Takara Bio, Otsu, Japan) was used as DNA polymerase for PCR as recommended by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

Hints to the diagnosis of uromodulin kidney disease

et al. 2015

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BackgroundUromodulin kidney disease (UKD) is an inherited kidney disease caused by a uromodulin (UMOD) gene mutation. The UMOD gene encodes the Tamm–Horsfall protein (THP), which is the most abundant protein in healthy human urine. Because of its rarity, the incidence of UKD has not been fully elucidated. The purpose of the present study is to clarify the frequency of UKD among patients who underwent renal biopsy.MethodsImmunostaining for THP was performed for patients <50 years of age with renal insufficiency and hyperuricemia without overt urinalysis abnormality from renal biopsy databases. Serum and urinary THP concentrations were evaluated in available individuals.ResultsFifteen patients were selected for immunostaining from a total of 3787 patients. In three independent patients, abnormal THP accumulation in renal tubular cells was observed. A novel missense A247P UMOD mutation was detected in two of the three patients, including one having a typical family history of familial juvenile hyperuricemic nephropathy. Serum and urinary THP concentrations of all available patients with UMOD A247P mutation were significantly lower than those of controls.ConclusionsIn the present study, UKD was detected in <1 in 1000 subjects who underwent renal biopsies. However, in subjects meeting all of the above criteria, abnormal THP accumulation was detected in 20% (3/15), suggesting that renal biopsy with immunostaining for THP is a good tool for diagnosing UKD. Also, low serum THP concentration detected in the present subjects might be a good diagnostic marker or important in understanding the pathogenesis of UKD.

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Section: Methodsmentioning

confidence: 99%

Hints to the diagnosis of uromodulin kidney disease

et al. 2015

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“…Eleven microsatellite markers with high proximity to PKD1 and PKD2 genes were used in this study. Onoe et al hypothesized that recombination would be easier to confirm in most cases by analyzing two highly heterozygous polymorphic markers on each side of the disease locus (Onoe et al 2003). Our selected markers for gene PKD2 lie on both sides of the locus, but markers for gene PKD1 were only proximal.…”

Section: Discussionmentioning

confidence: 99%

“…The age dependent manifestation of ADPKD makes imaging techniques less effective diagnostic tools than genetic studies. However, there is a role for genetic diagnosis in this disorder, especially in patients with equivocal imaging results, those with a negative family history and in cases where a definite diagnosis is required in younger individuals, such as for living related kidney donors (Onoe et al 2003).…”

Section: Introductionmentioning

confidence: 99%

DNA microsatellite analysis in families with autosomal dominant polycystic kidney disease (ADPKD): the first Polish study

et al. 2006

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“…Linkage analysis was performed using four CA-repeat markers for the PKD1 locus (D16S521, D16S3024, D16S3027, D16S423) and four for the PKD2 locus (D4S2964, D4S1534, D4S414, D4S1572) as described elsewhere (34). AmpliTaq gold DNA polymerase (PerkinElmer Life Sciences) and a universal touch-down thermal cycling program with GeneAmp PCR System Model 9600 (PE Applied Biosystems) was applied.…”

Section: Methodsmentioning

confidence: 99%

A Pathogenic C Terminus-truncated Polycystin-2 Mutant Enhances Receptor-activated Ca2+ Entry via Association with TRPC3 and TRPC7

Miyagi

Kiyonaka

Yamada

et al. 2009

Journal of Biological Chemistry

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Mutations in PKD2 gene result in autosomal dominant polycystic kidney disease (ADPKD). PKD2 encodes polycystin-2 (TRPP2), which is a homologue of transient receptor potential (TRP) cation channel proteins. Here we identify a novel PKD2 mutation that generates a C-terminal tail-truncated TRPP2 mutant 697fsX with a frameshift resulting in an aberrant 17-amino acid addition after glutamic acid residue 697 from a family showing mild ADPKD symptoms. When recombinantly expressed in HEK293 cells, wild-type (WT) TRPP2 localized at the endoplasmic reticulum (ER) membrane significantly enhanced Ca 2؉ release from the ER upon muscarinic acetylcholine receptor (mAChR) stimulation. In contrast, 697fsX, which showed a predominant plasma membrane localization characteristic of TRPP2 mutants with C terminus deletion, prominently increased mAChR-activated Ca 2؉ influx in cells expressing TRPC3 or TRPC7. Coimmunoprecipitation, pulldown assay, and cross-linking experiments revealed a physical association between 697fsX and TRPC3 or TRPC7. 697fsX but not WT TRPP2 elicited a depolarizing shift of reversal potentials and an enhancement of single-channel conductance indicative of altered ion-permeating pore properties of mAChR-activated currents. Importantly, in kidney epithelial LLC-PK1 cells the recombinant 679fsX construct was codistributed with native TRPC3 proteins at the apical membrane area, but the WT construct was distributed in the basolateral membrane and adjacent intracellular areas. Our results suggest that heteromeric cation channels comprised of the TRPP2 mutant and the TRPC3 or TRPC7 protein induce enhanced receptor-activated Ca 2؉

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An efficient linkage analysis strategy for autosomal dominant polycystic kidney disease

Cited by 4 publications

References 0 publications

Hints to the diagnosis of uromodulin kidney disease

Hints to the diagnosis of uromodulin kidney disease

DNA microsatellite analysis in families with autosomal dominant polycystic kidney disease (ADPKD): the first Polish study

A Pathogenic C Terminus-truncated Polycystin-2 Mutant Enhances Receptor-activated Ca2+ Entry via Association with TRPC3 and TRPC7

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