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

Cabrera-López C, Bullich G, Martí T, Català V, Ballarín J, Bissler JJ, Harris PC, Ars E, Torra R - BMC Med. Genet. (2015)

Bottom Line: Mutations 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.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.

View Article: PubMed Central - PubMed

Affiliation: Inherited Kidney Diseases, Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Cartagena 340-350, 08025, Barcelona, Spain. cristinacabrera79@hotmail.com.

ABSTRACT

Background: Mutations 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 results: We 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.

Conclusions: This 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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Related in: MedlinePlus

Panel a Pedigree of the family showing the segregation analysis of haplotypes as well as PKD1 and TSC2 mutations. The arrow points the proband reported in this case Panel b MLPA for PKD1 gene and the 3′ end of TSC2 gene, each bar represents the normalized peak height for the probe indicated on the x axis. The heavy black lines represent the deletion of the PKD1 exons 1–10 in heterozygosis. Panel c AML volume evolution: 1A and 1B baseline; 2A and 2B at the end of 3 years treatment with mTOR inhibitors; 3A and 3B one year later (without treatment). The AML decreased in size after 3 years on treatment and slightly increased in size one year after treatment withdrawal. Panel d Right (top row) and left kidney (bottom row): initial MR (1R and 1L), after 3 years on treatment with mTOR inhibitors (2R and 2L) and 1 year later (without treatment) (3R and 3L)
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Fig1: Panel a Pedigree of the family showing the segregation analysis of haplotypes as well as PKD1 and TSC2 mutations. The arrow points the proband reported in this case Panel b MLPA for PKD1 gene and the 3′ end of TSC2 gene, each bar represents the normalized peak height for the probe indicated on the x axis. The heavy black lines represent the deletion of the PKD1 exons 1–10 in heterozygosis. Panel c AML volume evolution: 1A and 1B baseline; 2A and 2B at the end of 3 years treatment with mTOR inhibitors; 3A and 3B one year later (without treatment). The AML decreased in size after 3 years on treatment and slightly increased in size one year after treatment withdrawal. Panel d Right (top row) and left kidney (bottom row): initial MR (1R and 1L), after 3 years on treatment with mTOR inhibitors (2R and 2L) and 1 year later (without treatment) (3R and 3L)

Mentions: His father, paternal aunt, paternal grandmother and sister have ADPKD (Fig. 1). The age at onset of ESRD was 68 for the grandmother, 44 for the father and 48 for the aunt. The patient’s sister has normal renal function, hypertension and enlarged kidneys (kidney length 17.5 cm) at the age of 30. There is no family history of TSC.Fig. 1


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

Cabrera-López C, Bullich G, Martí T, Català V, Ballarín J, Bissler JJ, Harris PC, Ars E, Torra R - BMC Med. Genet. (2015)

Panel a Pedigree of the family showing the segregation analysis of haplotypes as well as PKD1 and TSC2 mutations. The arrow points the proband reported in this case Panel b MLPA for PKD1 gene and the 3′ end of TSC2 gene, each bar represents the normalized peak height for the probe indicated on the x axis. The heavy black lines represent the deletion of the PKD1 exons 1–10 in heterozygosis. Panel c AML volume evolution: 1A and 1B baseline; 2A and 2B at the end of 3 years treatment with mTOR inhibitors; 3A and 3B one year later (without treatment). The AML decreased in size after 3 years on treatment and slightly increased in size one year after treatment withdrawal. Panel d Right (top row) and left kidney (bottom row): initial MR (1R and 1L), after 3 years on treatment with mTOR inhibitors (2R and 2L) and 1 year later (without treatment) (3R and 3L)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4631093&req=5

Fig1: Panel a Pedigree of the family showing the segregation analysis of haplotypes as well as PKD1 and TSC2 mutations. The arrow points the proband reported in this case Panel b MLPA for PKD1 gene and the 3′ end of TSC2 gene, each bar represents the normalized peak height for the probe indicated on the x axis. The heavy black lines represent the deletion of the PKD1 exons 1–10 in heterozygosis. Panel c AML volume evolution: 1A and 1B baseline; 2A and 2B at the end of 3 years treatment with mTOR inhibitors; 3A and 3B one year later (without treatment). The AML decreased in size after 3 years on treatment and slightly increased in size one year after treatment withdrawal. Panel d Right (top row) and left kidney (bottom row): initial MR (1R and 1L), after 3 years on treatment with mTOR inhibitors (2R and 2L) and 1 year later (without treatment) (3R and 3L)
Mentions: His father, paternal aunt, paternal grandmother and sister have ADPKD (Fig. 1). The age at onset of ESRD was 68 for the grandmother, 44 for the father and 48 for the aunt. The patient’s sister has normal renal function, hypertension and enlarged kidneys (kidney length 17.5 cm) at the age of 30. There is no family history of TSC.Fig. 1

Bottom Line: Mutations 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.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.

View Article: PubMed Central - PubMed

Affiliation: Inherited Kidney Diseases, Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, REDinREN, Instituto de Investigación Carlos III, Cartagena 340-350, 08025, Barcelona, Spain. cristinacabrera79@hotmail.com.

ABSTRACT

Background: Mutations 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 results: We 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.

Conclusions: This 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.

Show MeSH
Related in: MedlinePlus