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Nephronophthisis

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Abstract

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most frequent genetic cause of end-stage renal disease up to the third decade of life. It is caused by mutations in 11 different genes, denoted nephrocystins (NPHP1–11, NPHP1L). As an increasing number of these genes are identified, our knowledge of nephronophthisis is changing, thereby improving our understanding of the pathomechanisms in NPHP. Recent publications have described ciliary expression of nephrocystins together with other cystoproteins, such as polycystins 1 and 2 and fibrocystin. These findings have shifted our focus to a pathomechanism involving defects in ciliary function (ciliopathy) and planar cell polarity (PCP). In addition, discoveries of new nephrocystin genes have shown that the disease spectrum of NPHP is much broader than previously anticipated. Different forms of mutations within the same NPHP gene can cause different disease severity. In this review, we highlight the different hypotheses on the pathomechanisms for NPHP and underline the clinical variability of this disease. The clinical spectrum has become even more complex with the possibility of oligogenicity in NPHP.

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Acknowledgments

We thank Dr. Sandy Cope-Yokoyama (Department of Pathology, Children's Medical Center Dallas and UT Southwestern Medical Center, Dallas) for her contribution of the images of renal pathology in nephronophthisis and Dr. Michael Craig Morris (Department of Radiology, Children's Medical Center Dallas and UT Southwestern Medical Center, Dallas) for his contribution of the Joubert syndrome image.

F.H. is an investigator of the Howard Hughes Medical Institute, the Frederick G.L. Huetwell professor, and a Doris Duke Distinguished Clinical Scientist. He is supported by grants from the NIH (DK068306, DK064614 and DK069274). M.T.W. is a fellow of the Pediatric Scientist Development Program (PSDP) and was supported by grants from the Koeln Fortune Program Faculty of Medicine, University of Cologne (184/2004), the German Kidney Fund (Deutsche Nierenstiftung), the German Research Foundation (DFG WO 1229/2-1), and a T32 training grant.

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  1. Divison of Pediatric Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA

    Matthias T. F. Wolf

  2. Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA

    Friedhelm Hildebrandt

  3. Departments of Pediatrics, University of Michigan, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-5646, USA

    Friedhelm Hildebrandt

  4. Departments of Human Genetics, University of Michigan, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-5646, USA

    Friedhelm Hildebrandt

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Correspondence to Matthias T. F. Wolf.

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Wolf, M.T.F., Hildebrandt, F. Nephronophthisis. Pediatr Nephrol 26, 181–194 (2011). https://doi.org/10.1007/s00467-010-1585-z

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