Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies

König, Jens; Kranz, Birgitta; König, Sabine; Schlingmann, Karl Peter; Titieni, Andrea; Tönshoff, Burkhard; Habbig, Sandra; Pape, Lars; Häffner, Karsten; Hansen, Matthias; Büscher, Anja; Bald, Martin; Billing, Heiko; Schild, Raphael; Walden, Ulrike; Hampel, Tobias; Staude, Hagen; Riedl, Magdalena; Gretz, Norbert; Lablans, Martin; Bergmann, Carsten; Hildebrandt, Friedhelm; Omran, Heymut; Konrad, Martin

doi:10.2215/cjn.01280217

Cited by 83 publications

(113 citation statements)

References 43 publications

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“…Inflammation and fibrosis lead to a loss of parenchyma and small kidneys in patients with NPHP (Konig et al , ). In ADPKD, however, macrophages have been shown to be activators of cyst growth, thus leading to kidney enlargement and disease progression (Karihaloo et al , ), providing a rationale for the hypothesis that the regulatory effect of PKD1 and LKB1 on cilia‐induced CCL2 expression is relevant for human pathology.…”

Section: Resultsmentioning

confidence: 99%

“…Two of them have been linked to the renal ciliopathy nephronophthisis (NPHP): ANKS3 (ankyrin repeat and sterile alpha motif domain containing 3) and NEK7 (NIMA (never in mitosis gene A)-related kinase 7). ANKS3 is a ciliopathy protein and a known interactor of several proteins involved in NPHP, including NPHP1 (Leettola et al, 2014;Yakulov et al, 2015;Shamseldin et al, 2016), the protein mutated in 60% of patients with genetically defined NPHP (Hildebrandt et al, 1997;Saunier et al, 1997;Halbritter et al, 2013;Konig et al, 2017). ANKS3 also has a physical and functional interaction with NEK7, and NEK7 is part of the cilia proteome (Mick et al, 2015;Ramachandran et al, 2015).…”

Section: Lkb1 Interacts With Ciliopathy Proteins and A Functional Inmentioning

confidence: 99%

“…Inflammation and fibrosis lead to a loss of parenchyma and small kidneys in patients with NPHP (Konig et al, 2017). In ADPKD, however, macrophages have been shown to be activators of cyst ▸ Figure 5.…”

Section: Cilia-induced Ccl2 Promotes Disease Progression In a Mouse Mmentioning

confidence: 99%

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Cilia‐localized LKB 1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney

et al. 2018

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Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy‐related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells. Deletion of LKB1 or PKD1 in mouse renal tubules elevates CCL2 expression in a cell‐autonomous manner and results in peritubular accumulation of CCR2+ mononuclear phagocytes, promoting a ciliopathy phenotype. Our findings establish an epithelial organelle, the cilium, as a gatekeeper of tissue immune cell numbers. This represents an unexpected disease mechanism for renal ciliopathies and establishes a new model for how epithelial cells regulate immune cells to affect tissue homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Lkb1 Interacts With Ciliopathy Proteins and A Functional Inmentioning

confidence: 99%

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Cilia‐localized LKB 1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney

et al. 2018

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“…We present a case of nephronophthisis caused by compound heterozygous NPHP3 variants that presented at birth with kidney disease and cholestatic jaundice. NPHP3 mutations can cause neonatal kidney disease, hepatosplenomegaly, hypertension, and anemia (Bergmann et al, ; Konig et al, ; Olbrich et al, ; Penchev et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Pathology is caused by dysfunction or absence of the primary cilia, cellular projections present on multiple cell types that coordinate organ growth, patterning, and chemotransduction (Hildebrandt & Otto, ; Mitchinson & Valente, ). Pathology can be limited to the kidney; however, extra‐renal manifestations have been reported including congenital heart disease, liver fibrosis, situs inversus, retinopathy, and brain malformations (Bergmann et al, ; Fiskerstrand et al, ; Konig et al, ; Olbrich et al, ; Penchev et al, ; Waters & Beales, ).…”

Section: Introductionmentioning

confidence: 99%

Isosorbide dinitrate in nephronophthisis treatment

Strong

Muneeruddin

Parrish

et al. 2018

American J of Med Genetics Pt A

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Nephronophthisis is a progressive disease that affects development of the renal tubules and leads to end stage renal disease. Many affected children have isolated renal disease; however, there can be additional manifestations including heart defects, liver fibrosis, brain malformations, and situs inversus. There is no way to slow or modify the disease. We describe a patient who presented at birth with cholestatic jaundice and decreased kidney function, found by exome sequencing to have two NPHP3 variants. Her clinical status deteriorated rapidly, and two disease-modifying agents were given in hopes of slowing disease progression, the arginine vasopressin type II receptor antagonist tolvaptan to stabilize her renal function and isosorbide dinitrate to manage her poorly controlled hypertension. Tolvaptan therapy initiated at 82 days of life had limited effect on the rate of decline in renal function and was insufficient to abrogate the need for dialysis; however, isosorbide dinitrate therapy led to a dramatic improvement in blood pressure control and allowed for the discontinuation of multiple anti-hypertensive agents. This is the first report of the use of tolvaptan and isosorbide dinitrate for nephronophthisis management. We suggest that isosorbide dinitrate may represent a disease-modifying agent in nephronophthisis treatment.

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Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

Moller‐Hansen

Hejla

Lee

et al. 2023

American J of Med Genetics Pt A

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To date, PACS1-neurodevelopmental disorder (PACS1-NDD) has been associated with recurrent variation of Arg203 and is considered diagnostic of PACS1-NDD, an autosomal dominant syndromic intellectual disability disorder. Although incompletely defined, the proposed disease mechanism for this variant is altered PACS1 affinity for its client proteins. Given this proposed mechanism, we hypothesized that PACS1 variants that interfere with binding of adaptor proteins might also give rise to syndromic intellectual disability. Herein, we report a proposita and her mother with phenotypic features overlapping PACS1-NDD and a novel PACS1 variant (NM_018026.3:c.[755C > T];[=], p.(Ser252Phe)) that impedes binding of the adaptor protein GGA3 (Golgi-associated, gamma-adaptin ear-containing, ARF-binding protein 3). We hypothesize that attenuating PACS1 binding of GGA3 also gives rise to a disorder with features overlapping those of PACS1-NDD. This observation better delineates the mechanism by which PACS1 variation predisposes to syndromic intellectual disability.

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Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies

Abstract: Mutations in genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.

Cited by 83 publications

References 43 publications

Cilia‐localized LKB 1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney

Cilia‐localized LKB 1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney

Isosorbide dinitrate in nephronophthisis treatment

Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

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