<i>PKD1</i> mutation may epistatically ameliorate nephronophthisis progression in patients with <i>NPHP1</i> deletion

Watanabe, Saki; Ino, Jun; Fujimaru, Takuya; Taneda, Sekiko; Akihisa, Taro; Makabe, Shiho; Kataoka, Hiroshi; Mori, Takayasu; Sohara, Eisei; Uchida, Shinichi; Nitta, Kosaku; Mochizuki, Toshio

doi:10.1002/ccr3.1947

Cited by 3 publications

(5 citation statements)

References 25 publications

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“…For NPHP patients, no modifier gene has been identified. However, a recent case report showed that PKD1 mutation might epistatically ameliorate NPHP progression in patients with NPHP1 deletion [23]. In our case, no such NPHP-modifier variant was observed.…”

Section: Discussioncontrasting

confidence: 65%

A case report of NPHP1 deletion in Chinese twins with nephronophthisis

et al. 2020

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Background: Nephronophthisis (NPHP) is a rare autosomal recessive inherited disorder with high heterogeneity. The majority of NPHP patients progress to end-stage renal disease (ESRD) within the first three decades of life. As an inherited disorder with highly genetic heterogeneity and clinical presentations, NPHP still poses a challenging task for nephrologists without special training to make a well-judged decision on its precise diagnosis, let alone its mechanism and optimal therapy. Case presentation: A Chinese family with NPHP was recruited in current study. The clinical characteristics (including findings from renal biopsy) of NPHP patients were collected from medical records and the potential responsible genes were explored by the whole exome sequencing (WES). A homozygous deletion of NPHP1 (1-20 exons) was found in both affected patients, which was further confirmed by quantitative PCR. Conclusions: Homozygous full gene deletion of the NPHP1 gene was identified in a Chinese family with NPHP, which was the molecular pathogenic basis of this disorder. Furthermore, identification of the pathogenic genes for those affected patients can help to have a full knowledge on NPHP's molecular mechanism and precise treatment.

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Section: Discussioncontrasting

confidence: 65%

A case report of NPHP1 deletion in Chinese twins with nephronophthisis

et al. 2020

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“…Normalization of FBW7 levels restored renal function without a measurable effect on overall cystic index. Because disease progression in people with ADPKD and NPHP1 is milder compared to NPHP1 alone 41 , we speculate that similar effects will be seen in compound Pkd1/Nphp1 , Pkd1/Nphp4 , or Pkd1/Tmem237 mice.…”

Section: Discussionmentioning

confidence: 82%

“…The copyright holder for this preprint this version posted March 3, 2024. ; https://doi.org/10.1101/2024.02.29.582788 doi: bioRxiv preprint measurable effect on overall cystic index. Because disease progression in people with ADPKD and NPHP1 is milder compared to NPHP1 alone 41 , we speculate that similar effects will be seen in compound Pkd1/Nphp1, Pkd1/Nphp4, or Pkd1/Tmem237 mice.…”

Section: Discussionmentioning

confidence: 82%

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Patel,

Gerakopoulos,

Petsouki

et al. 2024

Preprint

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Nephronophthisis (NPHP) and autosomal dominant Polycystic Kidney Disease (ADPKD) are two genetically distinct forms of Polycystic Kidney Disease (PKD), yet both diseases present with kidney cysts and a gradual decline in renal function. Prevailing dogma in PKD is that changes in kidney architecture account for the decline in kidney function, but the molecular/cellular basis of such coupling is unknown. To address this question, we induced a form of proteome reprogramming by deleting Fbxw7 encoding FBW7, the recognition receptor of the SCFFBW7 E3 ubiquitin ligase in different segments of the kidney tubular system. Deletion of Fbxw7 in the medulla led to a juvenile-adult NPHP-like phenotype, where the decline in renal function was due to SOX9-mediated interstitial fibrosis rather than cystogenesis. In contrast, the decline of renal function in ADPKD is coupled to cystic expansion via the abnormal accumulation of FBW7 in the proximal tubules and other cell types in the renal cortex. We propose that FBW7 functions at the apex of a protein network that determines renal function in ADPKD by sensing architectural changes induced by cystic expansion.

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“…Mutations in these genes are associated with autosomal recessive polycystic kidney disease, Bardet-Biedl syndrome (BBS), and Joubert syndrome. Although these are autosomal recessive diseases, heterozygous point mutations in the genes may have had some effect on the homozygous NPHP1 mutation (11). Clin-Var (https://www.ncbi.nlm.nih.gov/clinvar/) reported that the mutation of IFT172 (p.Met560Val) is "likely benign," while that of BBS2 (p.Met645Thr) is of "uncertain significance" but had no data regarding the BBS1 mutation (p.Ile238Val).…”

Section: Discussionmentioning

confidence: 99%

“…Cases of NPH with NPHP1 gene mutations that show ESKD development in adulthood have rarely been reported ( 9 - 11 , 15 ). However, slowly progressive NPH, such as that observed in Case 2, may be underdiagnosed.…”

Section: Discussionmentioning

confidence: 99%

Different Clinical Courses of Nephronophthisis in Dizygotic Twins

et al. 2023

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Siblings with nephronophthisis occasionally show different clinical courses; however, the reasons for this remain unclear. We herein report cases of nephronophthisis in a pair of dizygotic twins with different clinical courses. The brother developed end-stage kidney disease at 17 years old; however, his sister did not show kidney insufficiency. Kidney biopsies revealed severe tubulointerstitial damage at 14 and 22 years old in the brother and sister, respectively. Both had a homozygous NPHP1 deletion with different heterozygous mutations related to hereditary cystic kidney disease. Since the dizygotic twins were exposed to similar environmental factors, genetic factors may have influenced their clinical course more strongly than environmental factors.

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PKD1 mutation may epistatically ameliorate nephronophthisis progression in patients with NPHP1 deletion

Cited by 3 publications

References 25 publications

A case report of NPHP1 deletion in Chinese twins with nephronophthisis

A case report of NPHP1 deletion in Chinese twins with nephronophthisis

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Different Clinical Courses of Nephronophthisis in Dizygotic Twins

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