Tuberous sclerosis complex and polycystic kidney disease together: An exception to the contiguous gene syndrome

Woerner, Audrey C.; Au, Kit Sing; Williams, Aimee T.; Harris, Peter C.

doi:10.1097/01.gim.0000204466.34876.d5

Cited by 9 publications

(4 citation statements)

References 11 publications

(24 reference statements)

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“…TCS2 , PDK1 and HNF1b ) involved in cystic kidney diseases by qRT-PCR using E16.5 and NB kidneys. It has been shown that the expression of some of these genes such as TCS2 was regulated by Wnt11 [25–27]. The qRT-PCR data revealed age-dependent and Wnt11 −/− dependent changes in the expression of several of the examined genes (Additional file 4: Figure S3).…”

Section: Resultsmentioning

confidence: 95%

Impairment of Wnt11 function leads to kidney tubular abnormalities and secondary glomerular cystogenesis

Nagy

Naillat

et al. 2016

BMC Dev Biol

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BackgroundWnt11 is a member of the Wnt family of secreted signals controlling the early steps in ureteric bud (UB) branching. Due to the reported lethality of Wnt11 knockout embryos in utero, its role in later mammalian kidney organogenesis remains open. The presence of Wnt11 in the emerging tubular system suggests that it may have certain roles later in the development of the epithelial ductal system.ResultsThe Wnt11 knockout allele was backcrossed with the C57Bl6 strain for several generations to address possible differences in penetrance of the kidney phenotypes. Strikingly, around one third of the null mice with this inbred background survived to the postnatal stages. Many of them also reached adulthood, but urine and plasma analyses pointed out to compromised kidney function. Consistent with these data the tubules of the C57Bl6 Wnt11−/− mice appeared to be enlarged, and the optical projection tomography indicated changes in tubular convolution. Moreover, the C57Bl6 Wnt11−/− mice developed secondary glomerular cysts not observed in the controls. The failure of Wnt11 signaling reduced the expression of several genes implicated in kidney development, such as Wnt9b, Six2, Foxd1 and Hox10. Also Dvl2, an important PCP pathway component, was downregulated by more than 90 % due to Wnt11 deficiency in both the E16.5 and NB kidneys. Since all these genes take part in the control of UB, nephron and stromal progenitor cell differentiation, their disrupted expression may contribute to the observed anomalies in the kidney tubular system caused by Wnt11 deficiency.ConclusionsThe Wnt11 signal has roles at the later stages of kidney development, namely in coordinating the development of the tubular system. The C57Bl6 Wnt11−/− mouse generated here provides a model for studying the mechanisms behind tubular anomalies and glomerular cyst formation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-016-0131-z) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 95%

Impairment of Wnt11 function leads to kidney tubular abnormalities and secondary glomerular cystogenesis

Nagy

Naillat

et al. 2016

BMC Dev Biol

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“…The MLPA assay will be useful in all TSC patients with significant renal cystic disease to differentiate CGS cases from those with TSC and PKD inherited as separate gene mutations 24,25. Approximately 60% of TSC cases are de novo; 80% due to TSC2 mutation,26 and practically all described CGS cases are de novo or inherited from a mosaic case 18.…”

Section: Discussionmentioning

confidence: 99%

Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome

Consugar

Wong

Lundquist

et al. 2008

Kidney International

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103

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Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.

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“…A case with separate TSC1 and PKD2 mutations had a very modest cystic phenotype, probably due to the relatively mild disease in PKD2 compared to PKD1 and because TSC1 mutations are rarely associated with renal cysts [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated

et al. 2015

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BackgroundMutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), while mutations in PKD1 or PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). PKD1 lays immediately adjacent to TSC2 and deletions involving both genes, the PKD1/TSC2 contiguous gene syndrome (CGS), are characterized by severe ADPKD, plus TSC. mTOR inhibitors have proven effective in reducing angiomyolipoma (AML) in TSC and total kidney volume in ADPKD but without a positive effect on renal function.Methods and resultsWe describe a patient with independent truncating PKD1 and TSC2 mutations who has the expected phenotype for both diseases independently instead of the severe one described in PKD1/TSC2-CGS. Treatment with mTOR inhibitors reduced the AML and kidney volume for 2 years but thereafter they resumed growth; no positive effect on renal function was seen throughout. This is the first case addressing the response to mTOR treatment when independent truncating mutations in PKD1 and TSC2 are present.ConclusionsThis case reveals that although PKD1 and TSC2 are adjacent genes and there is likely cross-talk between the PKD1 and TSC2 signalling pathways regulating mTOR, having independent TSC2 and PKD1 mutations can give rise to a milder kidney phenotype than is typical in PKD1/TSC2-CGS cases. A short-term beneficial effect of mTOR inhibition on AML and total kidney volume was not reflected in improved renal function.

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Tuberous sclerosis complex and polycystic kidney disease together: An exception to the contiguous gene syndrome

Cited by 9 publications

References 11 publications

Impairment of Wnt11 function leads to kidney tubular abnormalities and secondary glomerular cystogenesis

Impairment of Wnt11 function leads to kidney tubular abnormalities and secondary glomerular cystogenesis

Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome

Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated

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