Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

O’Toole, John F.; Liu, Yangjian; Davis, Erica E.; Westlake, Christopher J.; Attanasio, Massimo; Seelow, Dominik; Nürnberg, Gudrun; Becker, Christian; Nuutinen, Matti; Kärppä, Mikko; Ignatius, Jaakko; Uusimaa, Johanna; Pakanen, Salla; Jaakkola, E.; Heuvel, Lambertus P. van den; Fehrenbach, Henry; Wiggins, Roger C.; Zhou, Weibin; Wolf, Matthias; Wise, Eric L.; Helou, Juliana; Allen, Susan J.; Murga‐Zamalloa, Carlos; Ashraf, Shazia; Chaki, Moumita; Heeringa, Saskia F.; Chernin, Gil; Hoskins, Bethan E.; Chaı̈b, Hassan; Gleeson, Joseph G.; Kusakabe, Takehiro; Suzuki, Takehiko; Isaac, R. Elwyn; Quarmby, Lynne M.; Tennant, Bryan; Fujioka, Hisashi; Tuominen, Hannu; Hassinen, Ilmo E.; Lohi, H.; Houten, Judith L. Van; Rötig, Agnès; Sayer, John A.; Rolinski, Boris; Freisinger, Peter; Madhavan, Sethu M.; Herzer, Martina; Madignier, Florence; Prokisch, Holger; Nürnberg, Peter; Jackson, Peter K.; Khanna, Hemant; Katsanis, Nicholas; Hildebrandt, Friedhelm

doi:10.1172/jci40076c1

Cited by 4 publications

(5 citation statements)

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“…In humans, Icp55 is termed aminopeptidase 3 (APP3 or XPNPEP3) (Figure 4A). Mutations in the XPNPEP3 gene can lead to cystic kidney disease with ciliary dysfunction (O'Toole et al, 2010), suggesting a so-far-unknown connection between mitochondrial function and cilia. Future studies will have to address the molecular role of human APP3/XPNPEP3 in mitochondrial protein homeostasis.…”

Section: Cell Metabolismmentioning

confidence: 99%

The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease

et al. 2014

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Mitochondria fulfill central functions in bioenergetics, metabolism, and apoptosis. They import more than 1,000 different proteins from the cytosol. It had been assumed that the protein import machinery is constitutively active and not subject to detailed regulation. However, recent studies indicate that mitochondrial protein import is regulated at multiple levels connected to cellular metabolism, signaling, stress, and pathogenesis of diseases. Here, we discuss the molecular mechanisms of import regulation and their implications for mitochondrial homeostasis. The protein import activity can function as a sensor of mitochondrial fitness and provides a direct means of regulating biogenesis, composition, and turnover of the organelle.

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Section: Cell Metabolismmentioning

confidence: 99%

The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease

et al. 2014

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“…Interestingly, 25% of DKD patients positive for pathogenic or likely pathogenic variants were found to carry rare variants in known ciliopathy-associated genes, including 3 patients found to harbor rare putative loss-of-function variants in C5orf42 , a gene that is associated with rare autosomal recessive ciliopathies characterized by cystic kidney disease [48-50]. Similarly, we identified rare, likely pathogenic variants in XPNPEP3 in 2 DKD patients with ESRD; defects in XPNPEP3 cause nephronophthisis-like nephropathy, a cystic kidney disease that leads to ESRD [51]. Taken together, these data suggest that variants in kidney disease-related genes in the context of diabetic pathophysiology play a role in the pathogenesis of kidney disease in patients with diabetes.…”

Section: Discussion/conclusionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Diabetic Kidney Disease

Fierro-Morales

Wright

et al. 2021

Am J Nephrol

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Introduction: Diabetes is the most common cause of chronic kidney disease (CKD). For patients with diabetes and CKD, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes. Without histopathological confirmation, however, the underlying cause of their disease is unclear. Recent studies have shown that next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease. Methods: Here, we set out to investigate the genetic basis of disease in nondiabetic kidney disease (NDKD) and diabetic kidney disease (DKD) patients by performing targeted NGS using a custom panel comprising 345 kidney disease-related genes. Results: Our analysis identified rare diagnostic variants based on ACMG-AMP guidelines that were consistent with the clinical diagnosis of 19% of the NDKD patients included in this study. Similarly, 22% of DKD patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel. Genetic variants suggestive of NDKD were detected in 3% of the diabetic patients included in this study. Discussion/Conclusion: Our findings suggest that rare variants in kidney disease-related genes in a diabetic background may play a role in the pathogenesis of DKD and NDKD in patients with diabetes.

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“…49,78 These genes include NPHP1 , Inversin/NPHP2 , NPHP3, NPHP4, IQCB1/NPHP5, CEP290/NPHP6, GLIS2/NPHP7, RPGRIP1L/NPHP8, NEK8/NPHP9, SDCAAG8/NPHP10, TMEM67/NPHP11, TTC21B/NPHP12 , and WDR19/NPHP13 . 4,15,40,117 The proteins encoded by these genes are generally referred to as nephrocystins, and with the exception of NPHP-like 1 gene (NPHPL1) , which encodes a mitochondrial enzyme (X-prolyl aminopeptidase 3), 61 they have all been localized to the cilium/centrosome/basal body complex. This led to the conclusion that NPHP should be considered a ciliopathy.…”

Section: Discussionmentioning

confidence: 99%

Nephronophthisis and Retinal Degeneration inTmem218^–/–Mice

et al. 2014

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Mice deficient in TMEM218 (Tmem218 -/-) were generated as part of an effort to identify and validate pharmaceutically tractable targets for drug development through large-scale phenotypic screening of knockout mice. Routine diagnostics, expression analysis, histopathology, and electroretinogram analyses completed on Tmem218 -/-mice identified a previously unknown role for TMEM218 in the development and function of the kidney and eye. The major observed phenotypes in Tmem218 -/-mice were progressive cystic kidney disease and retinal degeneration. The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy and disruption of tubular basement membranes in essentially normal-sized kidneys. The retinal lesions were characterized by slow-onset loss of photoreceptors, which resulted in reduced electroretinogram responses. These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. At least 10% of NPHP cases present with extrarenal conditions, which most often include retinal degeneration. Senior-Løken syndrome is characterized by the concurrent development of autosomal recessive NPHP and retinitis pigmentosa. Since mutations in the known NPHP genes collectively account for only about 30% of NPHP cases, it is possible that TMEM218 could be involved in the development of similar ciliopathies in humans. In reviewing all other reported mouse models of NPHP, we suggest that Tmem218 -/-mice could provide a useful model for elucidating the pathogenesis of cilia-associated disease in both the kidney and the retina, as well as in developing and testing novel therapeutic strategies for Senior-Løken syndrome.

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Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

Abstract: Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

Cited by 4 publications

References 0 publications

The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease

The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease

Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Diabetic Kidney Disease

Nephronophthisis and Retinal Degeneration inTmem218^–/–Mice

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Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

Abstract: Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

Cited by 4 publications

References 0 publications

The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease

The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease

Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Diabetic Kidney Disease

Nephronophthisis and Retinal Degeneration inTmem218–/–Mice

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Nephronophthisis and Retinal Degeneration inTmem218^–/–Mice