Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis

Karsay, Rebeka; Schlingmann, Karl‐Peter; Telgmann, Anna-Katharina; Ariceta, Gema; Gillion, Valentine; Böckenhauer, Detlef; Bertholet‐Thomas, Aurélia; Mastrangelo, Antonio; Boyer, Olivia; Lilien, Marc R.; Decramer, Stéphane; Schanstra, Joost P.; Pöhl, Martin; Schild, Raphael; Hoefele, Julia; Hansen, Matthias; Thumfart, Julia; Tönshoff, Burkhard; Habbig, Sandra; Bald, Martin; Antczak, P.; Birtel, Johannes; Bergmann, Carsten; Cetiner, Metin; Dahmer-Heath, Mareike; Drube, Jens; Gerß, Joachim; Haffner, Dieter; Illig, Thomas; Kamp-Becker, I.; Klopp, Norman; Kollmann, Sabine; König, Jens; Konrad, Martin; Liebau, Max C.; Nittel, C.; Okorn, C.; Omran, Heymut; Pape, Lars; Pennekamp, Petra; Schäfer, Franz; Schermer, Bernhard; Storf, H.; Vasseur, J.; Weber, Stefanie; Wohlgemuth, Kai; Ziegler, Wolfgang; Gimpel, Charlotte; Göbel, Joe Hannah; Schlevogt, B.

doi:10.1016/j.ekir.2022.05.035

Cited by 8 publications

(3 citation statements)

References 66 publications

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“…For example, a most recent study reported that biallelic truncating variants in NPHP4 and NPHP1 were associated with a significantly worse kidney outcome compared with those carrying at least one missense variant in the corresponding genes. 26 As mentioned above, liver/bile duct abnormalities were important phenotypes of ANKS6-related NPHP, which were exclusively seen in those with two null ANKS6 alleles. Thus, it seems that ANKS6…”

Section: Discussionmentioning

confidence: 88%

“…Similar genotype–phenotype correlations have been reported in nephronophthisis caused by mutations in other genes. For example, a most recent study reported that biallelic truncating variants in NPHP4 and NPHP1 were associated with a significantly worse kidney outcome compared with those carrying at least one missense variant in the corresponding genes 26 …”

Section: Discussionmentioning

confidence: 99%

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Biallelic ANKS6 null variants cause notable extrarenal phenotypes in a nephronophthisis patient and lead to hepatobiliary abnormalities by YAP1 deficiency

et al. 2023

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The ankyrin repeat and sterile alpha motif domain containing 6 (ANKS6) gene, encoding an inversin compartment protein of the primary cilium, was recently reported as a pathogenic gene of nephronophthisis (MIM PS256100). Extrarenal manifestations are frequently observed in this disease, however, potential genotype–phenotype correlations and the underlying mechanisms remain poorly understood. Here we described an infant with kidney failure, hepatobiliary abnormalities, and heart disease, in whom whole exome sequencing identified compound heterozygous variants in ANKS6, including a novel nonsense variant p.Trp458* and a recurrent splicing variant c.2394+1G > A. mRNA expression studies showed that the splicing variant caused aberrant mRNA splicing with exon 13 skipping and the biallelic variants were predicted to cause loss of ANKS6 function. We systematically characterized the clinical and genetic spectra of the disease and revealed that biallelic null variants in ANKS6 cause more severe kidney disease and more extrarenal manifestations, thus establishing a clear genotype–phenotype correlation for the disease. Further evaluations showed that ANKS6 deficiency reduced YAP1 expression in the patient's bile duct epithelium and ANKS6 promotes YAP1 transcriptional activity in a dose‐dependent manner, indicating that loss of ANKS6 function causes hepatobiliary abnormalities through YAP1 deficiency during biliary morphogenesis and development, which may offer new therapeutic targets.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Biallelic ANKS6 null variants cause notable extrarenal phenotypes in a nephronophthisis patient and lead to hepatobiliary abnormalities by YAP1 deficiency

et al. 2023

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“… 13 , 14 Moreover, a cohort study of nephronophthisis suggested that the use of angiotensin-converting enzyme inhibitors was an independent risk factor associated with early-onset ESRD in patients with pathological variants of NPHP1 . 15 Therefore, accurately diagnosing inherited kidney diseases may delay CKD progression and avoid RRT. Furthermore, in inherited kidney diseases with extrarenal complications, such as Fabry disease, autosomal dominant polycystic kidney disease (ADPKD), and nephronophthisis, an accurate genetic diagnosis is important for the early evaluation and prevention of complications.…”

mentioning

confidence: 99%