Molecular Pathogenesis
Almost all nephronophthisis-related genes (NPH-related genes) encode proteins localized to the cilium at the ciliary transition zone, the inversin compartment, or subunits of the IFT complexes where they are involved in ciliogenesis and regulation of ciliary protein trafficking [Fliegauf et al 2006, Omran 2010, Novarino et al 2011, Sang et al 2011, van Reeuwijk et al 2011]. In addition, the protein products of NPHP1, INVS, and NPHP4 localize to and regulate cell-cell junctions [Donaldson et al 2002, Delous et al 2009, Hurd & Hildebrandt 2011].
The mechanism by which disruption in these NPH-related proteins leads to nephronophthisis is unknown, although recent studies have shed light on nephrocystin functions and associated pathways. Nephrocystins are implicated in important signaling pathways, such as the Wnt pathway (involved in apical-basolateral polarity of renal tubular cells in response to tubular flow) [Simons et al 2005], the Hedgehog pathway (involved in mesenchymal-to-epithelial transition in renal tubulogenesis) [Yu et al 2002, Attanasio et al 2007], and the Hippo pathway (involved in regulation of tissue growth) [Benzing & Schermer 2012, Barker et al 2014, Wolf 2015].
In addition, the NPH-related genes NEK8, CEP164, SDCCAG8, CEP290, and ZNF423 play a dual role in the nucleus and have been implicated in DNA damage response (DDR) signaling [Chaki et al 2012, Zalli et al 2012, Choi et al 2013, Yuan & Sun 2013, Airik et al 2014, Slaats et al 2014, Slaats & Giles 2015, Slaats et al 2015]. As pathogenic variants in CEP164 induce epithelial-to-mesenchymal transition and a profibrotic response [Slaats et al 2014], the DDR pathway may be most closely linked to tubulointerstitial fibrosis, a hallmark feature of nephronophthisis [Slaats & Giles 2015].
Cilia are present on nearly all cell types, and pathogenic variants in NPH-related genes affect cilia function in a tissue-specific manner [Garcia-Gonzalo et al 2011, Benzing & Schermer 2012], accounting for the wide variety of extrarenal manifestations in nephronophthisis-related ciliopathies.
The considerable inter- and intrafamilial variability in the associated extrarenal manifestations and the rate of progression to ESRD may be due to the degree of protein impairment and the contribution of genetic modifiers [Caridi et al 2006, Hoefele et al 2007, Littink et al 2010, Drivas et al 2015]. Oligogenic inheritance has been described in several NPH-related ciliopathies [Katsanis et al 2001, Badano et al 2003, Baala et al 2007b, Helou et al 2007, Tory et al 2007, Leitch et al 2008, Louie et al 2010, Davis et al 2011, Lin et al 2013, Zhang et al 2014]. Note that some proposed modifier alleles occur frequently in control populations and, therefore, their own pathogenicity is debatable (e.g., see the ExAC Browser).
Examples of proposed genetic modifiers for NPH-related genes include the following:
A
heterozygous truncating variant in
CEP290 in one person and heterozygous
missense variants in
AHI1 in six persons with
homozygous NPHP1 deletions [
Tory et al 2007]. Variants in
CEP290 and
AHI1 were hypothesized to contribute to neurologic findings in these seven individuals who had
biallelic NPHP1 pathogenic variants.
An enrichment of pathogenic variants in
TTC21B in individuals with a ciliopathy, suggesting a modifier role for
TTC21B [
Davis et al 2011].
Note: To date no heterozygous NPHP1 pathogenic variant has been identified as a modifier in isolated nephronophthisis caused by biallelic pathogenic variants in another NPH-related gene.
For a detailed summary of gene and protein information for the genes discussed in this section, see Table A, Gene.
NPHP1
Gene structure.
NPHP1 comprises 20 exons and is alternatively spliced in 11 variants. The largest transcript is NM_000272. It encodes a 732-amino acid product. NPHP1 is flanked by segmental duplications that are prone to nonallelic homologous recombination [Saunier et al 2000].
Benign variants.
Saunier et al [2000] demonstrated a benign rearrangement involving the two 330-kb inverted repeats surrounding the common 290-kb deletion in homozygous state in two controls (1.3%).
NPHP1 duplications have been described in persons with autism spectrum disorders and developmental delay without associated renal features [Baris et al 2006, Yasuda et al 2014].
Pathogenic variants. The common NPHP1 290-kb deletion (which includes the entire gene) is found in the homozygous state in 20%-25% of persons with nephronophthisis [Hildebrandt et al 2009, Halbritter et al 2013].
Other loss-of-function pathogenic variants, such as p.Leu27Ter, occur in the compound heterozygous state with the common deletion in individuals with NPH [Saunier et al 1997, Hildebrandt et al 1997].
Modifier variants. It has been proposed that heterozygous pathogenic variants act as modifier alleles in Bardet-Biedl syndrome [Lindstrand et al 2014].
Table 4.
NPHP1 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
NPHP1 encodes nephrocystin 1, which localizes to the ciliary transition zone. The C-terminal region mediates NPHP1 localization to cell-cell junctions, interaction with filamins, establishment of cell polarity, and interaction of with NPHP4 [Donaldson et al 2002, Mollet et al 2005].
Abnormal gene product. Loss of NPHP1 function causes disease. For information on animal models click here.
INVS (NPHP2)
Gene structure.
INVS comprises 17 exons. It has eight transcripts of which the longest is NM_014425.
Pathogenic variants. Biallelic truncating and missense pathogenic variants cause infantile and juvenile NPH [Gagnadoux et al 1989, Otto et al 2003, Tory et al 2009, Chaki et al 2011, Halbritter et al 2013].
Two individuals with compound heterozygous INVS truncating pathogenic variants had isolated juvenile-onset NPH (c.1417delG, c.3125delA, c.2695C>T, c.2782C>T) [Halbritter et al 2013]. There was no clear correlation between the type of pathogenic variant and the presence or severity of situs inversus or other extrarenal ophthalmologic, central nervous system, and cardiac features [Otto et al 2003, O'Toole et al 2006, Otto et al 2008, Tory et al 2009, Chaki et al 2011].
Table 5.
INVS Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
INVS encodes a 1,065-amino acid protein. INVS contains several domains and protein-binding motifs, including 16 ankyrin repeats, two IQ domains (including 1 calmodulin-binding domain), two D boxes (including 1 anaphase-promoting complex subunit-2 [APC2]-binding D box), and a bipartite nuclear localization signal (NLS-BP) [Morgan et al 2002a, Morgan et al 2002b, Schön et al 2002, Otto et al 2003]. INVS localizes to and defines the INVS compartment.
INVS:
Is involved in regulation of ciliary disassembly through phosphorylation and inhibition of Aurora A, a cell cycle kinase that promotes ciliary disassembly [
Mergen et al 2013];
Abnormal gene product. See Animal Models.
NPHP3
Gene structure.
NPHP3 comprises 27 exons. It has 14 different transcripts. The longest transcript, NM_153240, encodes a protein of 1,330 amino acids.
Pathogenic variants. Homozygous pathogenic variants in NPHP3 cause infantile-onset, juvenile-onset, and adolescent-onset NPH [Olbrich et al 2003, Simpson et al 2009, Tory et al 2009, Halbritter et al 2013].
The homozygous nonsense pathogenic variant p.Arg702Ter was identified in 12 infants from six Amish families with neonatal lethal NPH [Simpson et al 2009].
NPHP3 pathogenic variants were identified in children with infantile-onset NPH [Simpson et al 2009, Tory et al 2009, Halbritter et al 2013] and in two families with Meckel-Gruber syndrome [Bergmann et al 2008, Tory et al 2009].
Homozygous in-frame deletion of three base pairs in NPHP3 (p.Gly1275del) was first detected in a Venezuelan family with adolescent-onset NPH [Olbrich et al 2003].
Brain and cardiac anomalies have been associated with biallelic nonsense pathogenic variants [Chaki et al 2011]. Liver fibrosis is a common extrarenal feature [Tory et al 2009, Halbritter et al 2013].
Table 6.
NPHP3 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.2104C>T | p.Arg702Ter |
NM_153240.4
NP_694972.3
|
c.3824_3826delGAG | p.Gly1275del | |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. The longest NPHP3 transcript encodes a protein of 1,330 amino acids.
NPHP3:
Contains a coiled coil
domain, a tubulin-tyrosine ligase domain, and a tetratrico peptide repeat (TPR) domain that is predicted at the site of interaction with NPHP1 [
Olbrich et al 2003];
Interacts in a complex with the proteins NEK8, INVS, and ANKS6 [
Hoff et al 2013];
Abnormal gene product. See Animal Models.
NPHP4
Gene structure.
NPHP4 comprises 30 exons. It is expressed in ten splice variants. The largest transcript is NM_015102, which encodes a protein of 1,426 amino acids.
Pathogenic variants. Numerous missense, nonsense, and splicing variants and small indels have been described. Pathogenic variants are associated with isolated juvenile-onset NPH [Mollet et al 2002, Otto et al 2002] and were associated with Senior-Løken syndrome in two families homozygous for the nonsense pathogenic variants p.Arg658Ter and p.Gln779Ter [Otto et al 2002].
While there is a correlation between the presence of extrarenal features (involving the eye, liver, and developmental delay) and mutation of NPHP4 in general, no clear correlation between the presence of these features and a specific NPHP4 variant type (e.g., missense, nonsense) has been found [Chaki et al 2011].
Table 7.
NPHP4 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
NPHP4 encodes the 1,426-amino acid protein nephrocystin-4, which is part of the ciliary transition zone.
NPHP4:
May be involved in actin cytoskeleton organization at sites of cell-cell and cell-matrix adhesion [
Mollet et al 2005].
Abnormal gene product. See Animal Models.
IQCB1 (NPHP5)
Gene structure.
IQCB1 (NPHP5) consists of 15 exons and has seven alternatively spliced transcripts. The largest transcript is NM_001023570, which encodes a protein of 598 amino acids.
Pathogenic variants. Biallelic missense, nonsense, and splice-site pathogenic variants and small indels in IQCB1 are associated with Senior-Løken syndrome [Otto et al 2005] and Leber congenital amaurosis [Stone et al 2011].
The phenotype of 33 individuals with biallelic nonsense or splice-site pathogenic variants in IQCB1 comprised juvenile NPH and early-onset retinal degeneration. None had severe central nervous system or liver anomalies [Chaki et al 2011].
Modifier variant. The p.Ile393Asn variant, which is not associated with a renal phenotype, was identified as a modifier of RPGR-related retinitis pigmentosa [Fahim et al 2012].
Table 8.
IQCB1 Modifier Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
IQCB1 encodes a protein of 598 amino acids.
IQCB1:
Contains two putative IQ calmodulin-binding domains that flank a coiled-coil
domain;
Abnormal gene product. See Animal Models.
CEP290 (NPHP6)
Gene structure.
CEP290 (NPHP6) comprises 54 exons and eight splice variants. NM_025114 is the longest transcript.
Pathogenic variants. Pathogenic variants in CEP290 are associated with Senior-Løken syndrome, Joubert syndrome [Sayer et al 2006, Valente et al 2006], Leber congenital amaurosis [den Hollander et al 2006], Bardet-Biedl syndrome [Leitch et al 2008], and Meckel-Gruber syndrome [Baala et al 2007b].
The majority of reported CEP290 pathogenic variants are inactivating: in a review of 112 pathogenic variants, 88 were truncating, 20 were predicted to influence splicing, and three were missense [Coppieters et al 2010].
In 26 individuals with CEP290 biallelic pathogenic variants, 24 developed juvenile-onset NPH and two developed infantile-onset NPH; all 26 exhibited extrarenal manifestations [Chaki et al 2011].
Table 9.
Selected CEP290 Pathogenic Variants
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product. The centromere protein CEP290 is 2,479 amino acids long.
CEP290:
Abnormal gene product. See Animal Models.
TMEM67 (NPHP11)
Gene structure.
TMEM67 (NPHP11) comprises 28 exons and has 22 transcripts. The longest transcript, NM_153704, encodes a 995-amino acid protein.
Pathogenic variants. More than 100 pathogenic variants in TMEM67 have been described.
Biallelic TMEM67 pathogenic variants are associated with a variety of ciliopathies () ranging from NPH with hepatic fibrosis at the mild end of the spectrum (biallelic missense variants) [Otto et al 2009, Chaki et al 2011] to Joubert syndrome [Baala et al 2007b, Otto et al 2009], COACH syndrome [Verloes & Lambotte 1989, Brancati et al 2009], and Meckel-Gruber syndrome at the severe end of the spectrum (characterized by a higher prevalence of truncating variants) [Smith et al 2006, Consugar et al 2007]. Liver disease is a common feature in TMEM67-related disease [Otto et al 2009].
Most individuals with TMEM67-related NPH have juvenile NPH; the missense variants c.755T>C (p.Met252Thr) and c.1843T>C (p.Cys615Arg) were identified in an individual with infantile-onset NPH [Chaki et al 2011].
Modifier variants. Heterozygous pathogenic variants in TMEM67 have been proposed as modifier alleles in Bardet-Biedl syndrome [Lindstrand et al 2014, Leitch et al 2008].
Table 10.
TMEM67 Variants Discussed in This GeneReview
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Variant Classification | DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
Pathogenic
| c.755T>C | p.Met252Thr |
NM_153704.5
NP_714915.3
|
c.1843T>C | p.Cys615Arg |
Modifier
| c.958A>T | p.Ser320Cys |
c.2241G>A | p.= |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
TMEM67 encodes a 995-amino acid protein that localizes to the basal body [Williams et al 2011]. TMEM67 interacts with MKS1, and this interaction is required for normal ciliogenesis in mouse IMCD3 cells and patient-derived renal cells [Dawe et al 2007, Tammachote et al 2009].
Abnormal gene product. Disruption of the interaction of the C-terminus region of TMEM67 with filamin A caused defects in basal body positioning, ciliogenesis, and the Wnt signaling pathway [Adams et al 2012]. See Animal Models.
GLIS2
See .
Table 11.
Selected GLIS2 Pathogenic Variants
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.523T>C | p.Cys175Arg |
NM_032575.2
NP_115964.2
|
c.775+1G>T | |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
RPGRIP1L
See .
A common p.Ala229Thr allele in RPGRIP1L was enriched in individuals with ciliopathies involving retinitis pigmentosa compared to other ciliopathies and may represent a modifier of retinal degeneration [Khanna et al 2009].
Table 12.
RPGRIP1L Modifier Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Additional Genetic Causes of Nephronophthisis
Additional genes less commonly associated with nephronophthisis (see ):
ANKS6
CEP83
CEP164
DCDC2
IFT172
NEK8
SDCCAG8
TTC21B
WDR19
ZNF423