Nephronophthisis

Abstract

Nephronophthisis (NPHP) is an autosomal recessive kidney disorder characterized by chronic tubulointerstitial nephritis and leading to end-stage renal failure. NPHP as a renal entity is often part of a multisystem disorder and has been associated with many syndromes including Joubert syndrome (and related disorders) and Senior-Loken syndrome. Recent molecular genetic advances have allowed identification of several genes underlying NPHP. Most of these genes express their protein products, named nephrocystins, in primary cilial/basal body structures. Some nephrocystins are part of adherens junction and focal adhesion kinase protein complexes. This shared localization suggests that common pathogenic mechanisms within the kidney underlie this disease. Functional studies implicate nephrocystins in planar cell polarity pathways, which may be crucial for renal development and maintenance of tubular architecture.

Figure 1

Ultrasound scan features of nephronophthisis. Renal ultrasound scan demonstrating corticomedullary cysts, some of which are arrowed.

Figure 2

Diagnostic algorithm for NPHP. Where there is clinical or radiological suspicion of NPHP, the NPHP1 gene should be screened first if onset of end-stage renal failure is greater than 5 years of age. NPHP1 mutations account for ∼25% of cases of NPHP. Infantile NPHP is rare (<1% of cases) but should be suspected, and the known genes screened, if there are clinical and radiological features suggestive of NPHP and age of end-stage renal failure is less than 5 years of age. If no mutations are found additional NPHP genes should be screened depending on phenotype and a differential diagnosis of MCKD, ARPKD and BBS should be considered.

Figure 3

Nephrocystin proteins and their protein domains. Domain structure of the nephrocystin proteins. Nephrocystin proteins contain a diverse variety of protein domains and no common pattern can be identified. Nephrocystin-1, encoded by NPHP1, is a 732 amino acid (aa) protein, which possesses an N-terminal coiled-coil domain (CC) and a Src-homology 3 domain (SH3). Nephrocystin-2 (alias inversin), encoded by NPHP2/INVS, is a 1260 aa protein with 16 tandem ankyrin repeats, two IQ calmodulin binding domains (IQ). There are two destruction-box (D-box) regions (the first of which is Apc2 binding) and a bipartite nuclear localization signal (b-NLS) and a putative coiled-coil (CC) domain. Nephrocystin-3, encoded by NPHP3, is a 1330 aa protein, with a coiled-coil domain (CC), a tetratricopeptide-repeat domain (TPR) and a tubulin tyrosine ligase domain (TTL). Within the TTL a STAND (signal transduction ATPases with numerous domains) domain, which may be found in P-loop NTPases, is located. Nephrocystin-4 (alias nephroretinin), encoded by NPHP4 is a 1426 aa protein, which lacks any known domains. There is a central proline rich region. Nephrocystin-5, encoded by NPHP5/IQCB1 is a 598 aa protein. This protein possesses two IQ calmodulin binding sites, which surround a putative coiled-coil (CC) domain. Nephrocystin-6 (alias CEP290) is encoded by NPHP6/CEP290. This is a 2479 aa protein with multiple domains which include 13 coiled-coil (CC) domains; 3 tropomyosin homology domains (TM); 6 RepA/Rep⁺ protein KID motifs (KID); a bipartite nuclear localization signal (b-NLS); a ATP/GTP-binding site motif A (p-loop). The extent of homology with Structural Maintenance of Chromosomes proteins (SMC) is also indicated. AHI1 (alias Jouberin) is encoded by AHI1 and is an 1196 aa protein, which contains a Src-homology 3 domain (SH3), 6 WD40 domains (WD40) and an N-terminal coiled-coil domain. GLIS family zinc finger 2 (alias nephrocystin-7) is a 524 aa protein encoded by GLIS2. It contains 5 zinc finger domains (ZnF). RPGRIP1L (alias nephrocystin-8) is a 1315 aa protein encoded by RPGRIP1L. Protein domains include 6 coiled-coil (CC) domains and two protein kinase C conserved region 2 (C2) domains. The C-terminal C2 domain mediates the interaction with nephrocystin-4. NEK8 (alias nephrocystin-9) is a 692 aa protein with a serine/threonine protein kinases, catalytic domain (S-TKc) and a regulator of chromosome condensation (RCC1) domain, which is highly conserved throughout evolution.