Alternative titles; symbols
HGNC Approved Gene Symbol: NPHP1
SNOMEDCT: 204958008, 444830001;
Cytogenetic location: 2q13 Genomic coordinates (GRCh38) : 2:110,123,348-110,205,013 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q13 | Joubert syndrome 4 | 609583 | Autosomal recessive | 3 |
| Nephronophthisis 1, juvenile | 256100 | Autosomal recessive | 3 | |
| Senior-Loken syndrome-1 | 266900 | Autosomal recessive | 3 |
The presence of large homozygous deletions of approximately 250 kb (607100.0005) in the 2q13 region in most patients with juvenile nephronophthisis (NPHP1; 256100) allowed Saunier et al. (1997) to define a minimal deletion interval for the NPH1 gene. They established a BAC contig covering this interval. A combination of large-scale genomic sequencing, cDNA selection, and computer-aided analysis led to the characterization of 2 transcriptional units. One encoded the already known BENE protein (602022), and the other encoded a novel protein of at least 732 amino acids containing a putative src homology-3 (SH3) domain. The latter was shown to be the NPHP1 gene.
Following up on the observation that 65 to 75% of NPH1 patients exhibit large homozygous deletions in the 2q13 region, Hildebrandt et al. (1997) identified 2 genes, called NPHP1 and MALL (for MAL-like; 602022) by them. (The MAL gene (188860) encodes the T-lymphocyte maturation-associated protein.) Hildebrandt et al. (1997) determined that the 4.5-kb NPHP1 transcript encodes a protein with an SH3 domain that is highly conserved throughout evolution. They found that the NPHP1 gene extends over most of the common deletion interval. The 11-kb interval between the 3-prime end of NPHP1 and an inverted repeat containing the distal deletion breakpoint was found to contain the first exon of the MALL gene.
Saunier et al. (1997) determined that the NPHP1 gene, which they identified as a novel gene in the nephronophthisis-1 interval on 2q13, contains at least 20 exons spanning more than 80 kb and is entirely located in the nonduplicated region common to all the NPHP1 deletions. Hildebrandt et al. (1997) likewise detected at least 20 exons, 18 of which have a median size of 95 basepairs.
The NPHP1 gene was identified in the minimal deletion interval on chromosome 2q13 for nephronophthisis-1 (Saunier et al., 1997; Hildebrandt et al., 1997).
Using a yeast 2-hybrid screen of an embryonic mouse cDNA library with the C-terminal region of BCAR1 (602941) as bait, Donaldson et al. (2000) detected interaction with the SH3 domain of mouse nephrocystin, which is 83% identical to human nephrocystin. By immunoprecipitation and Western blot analyses, Benzing et al. (2001) showed that nephrocystin interacts with p130Cas (BCAR1), proline-rich tyrosine kinase-2 (PTK2B; 601212), and tensin (TNS; 600076) in embryonic kidney and testis, indicating that these proteins participate in a common signaling pathway. Immunoblot analysis established that expression of nephrocystin induces phosphorylation of PTK2B on tyr402.
Mollet et al. (2005) showed that NPHP1 interacted with nephrocystin-4 (NPHP4; 607215) and that the last 79 residues of NPHP1 were required for NPHP4 interaction. NPHP4 interacted with BCAR1 and PTK2B similar to NPHP1, and both NPHP1 and NPHP4 localized with alpha-tubulin (see 602529) especially to the primary cilia and microtubule organizing center in MDCK cells. Mollet et al. (2005) suggested that NPHP1 and NPHP4 belong to a multifunctional complex localized in actin- and microtubule-based structures involved in cell-cell and cell-matrix adhesion signaling, as well as in cell division.
Delous et al. (2009) showed that nephrocystin mRNA expression was dramatically increased during cell polarization, and shRNA-mediated knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed tight junction (TJ) formation, abnormal cilia formation, and disorganized multilumen structures when grown in a 3-dimensional collagen matrix. Some of these phenotypes were similar to those reported for cells depleted of the TJ proteins PALS1 (MPP5; 606958) or PAR3 (PARD3; 606745). A physical interaction between these nephrocystins and PALS1 as well as their partners PATJ (INADL; 603199) and PAR6 (PARD6A; 607484) was demonstrated, and the proteins partially colocalized in human renal tubules. The authors concluded that the nephrocystins play an essential role in epithelial cell organization, suggesting a mechanism by which the histopathologic features of nephronophthisis might develop.
Williams et al. (2011) showed that the conserved proteins Mks1 (609883), Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67 (609884), Rpgrip1l (610937), Cc2d2a (612013), Nphp1, and Nphp4 functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.
Deletion at the NPHP1 Locus
Konrad et al. (1996) observed that mutation in the NPH1 gene appears to be responsible for the vast majority (approximately 85%) of the purely renal forms of juvenile nephronophthisis, that is, cases without extrarenal features such as ocular lesions. By haplotype analysis, Konrad et al. (1996) identified 2 DNA markers flanking the NPH1 gene at loci D2S1890 and D2S1888. This interval of approximately 2 cM and the surrounding region was cloned in a YAC contig. The region turned out to be partially duplicated on 2p12. Further, several markers mapped to more than 1 locus within the NPH1 region on 2q13, suggesting to them the presence of low copy repeats. As low copy repeats predispose to large-scale chromosomal rearrangements, Konrad et al. (1996) performed PCR analysis of sequence tagged sites (STSs) mapping to the region. By this approach, they detected large-scale rearrangements in 80% of the patients belonging to inbred or multiplex NPH1 families and in 65% of the sporadic cases. In most cases these rearrangements appeared to be large homozygous deletions of approximately 250 kb involving a 100-kb inverted duplication (607100.0005). This suggested a common genetic disease-causing mechanism that could be responsible for the highest frequency of large rearrangements reported in an autosomal recessive disorder. The authors stated that their findings were of major clinical interest because they permitted the diagnosis of the disorder in most sporadic cases, thus avoiding the need for kidney biopsy.
Hildebrandt et al. (1997) found that both the MALL and NPHP1 genes were homozygously deleted in patients from 16 of 22 families with nephronophthisis showing linkage to the 2q13 region.
Ala-Mello et al. (1998) studied 14 Finnish families with NPHP1. Deletions of the NPH1 locus were found in 12 patients from 9 families. Haplotype analysis using markers D2S340, D2S1889, and D2S1893 showed no evidence of a founder effect. Linkage analysis showed a lod score of 1.39 to 3.89 at theta = 0.0 in those families with a deletion with markers D2S176, D2S293, and D2S340. Linkage to 2q13 was excluded in those families with no deletion by combined lod score values between -4.7 and -1.69 at theta = 0.01. End-stage renal disease occurred at a more advanced age in patients without deletions.
Betz et al. (2000) reported 2 patients with nephronophthisis-1 associated with Cogan-type congenital ocular motor apraxia (COMA; 257550). One patient had large deletions on each chromosome 2q13, while the other had a deletion encompassing the NPHP1 gene on one chromosome 2q13 and a point mutation of the NPHP1 gene (607100.0004) in the other chromosome 2q13.
Caridi et al. (1998) demonstrated the association of nephronophthisis with retinitis pigmentosa (Senior-Loken syndrome; 266900) in patients with homozygous deletion in the NPHP1 gene.
By large-scale genomic sequencing and pulsed field gel electrophoresis analysis, Saunier et al. (2000) characterized the complex organization of the NPHP1 locus and determined the mutational mechanism that results in the large deletion that is found in approximately 80% of patients. They showed that the deletion is 290 kb long and that NPHP1 is flanked by 2 large inverted repeats of approximately 330 kb. In addition, a second sequence of 45 kb located adjacent to the proximal 330-kb repeat was shown to be directly repeated 250 kb away within the distal 330-kb repeat deleting a sequence tag site present in the proximal copy. The patients' deletion breakpoints appeared to be located within the 45-kb repeat, suggesting an unequal recombination between the 2 homologous copies of this smaller repeat. Moreover, in 11 patients, they demonstrated a nonpathologic rearrangement involving the two 330-kb inverted repeats, and the same rearrangement was found in homozygous state in 2 (1.3%) control individuals. This could be explained by interchromosomal mispairing of the 330-kb inverted repeat, followed by double recombination or by a prior intrachromosomal mispairing of these repeats, leading to an inversion of the NPHP1 region, followed by an interchromosomal unequal crossover event. This complex rearrangement, as well as the common deletion found in most patients, illustrates the high level of rearrangements occurring in the centromeric region of chromosome 2.
Joubert syndrome (JS; 213300) is an autosomal recessive multisystem disease characterized by cerebellar vermis hypoplasia with prominent superior cerebellar peduncles (resulting in the 'molar tooth sign,' or MTS, on axial MRI), mental retardation, hypotonia, irregular breathing pattern, and eye movement abnormalities. Some individuals with JS have retinal dystrophy and/or progressive renal failure characterized as nephronophthisis. The disorder in such patients is referred to as cerebellooculorenal syndrome, or CORS. Parisi et al. (2004) screened for mutations in the NPHP1 gene by standard methods in a cohort of 25 subjects with JS and renal and/or retinal complications and in 2 subjects with juvenile nephronophthisis only. Two sibs with a mild form of JS had a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with nephronophthisis alone.
Mutation of the NPHP1 gene
In 2 patients carrying the large deletion of the NPH1 region on only 1 allele, Saunier et al. (1997) detected 2 mutations in 2 independent exons of the NPHP1 gene. One consisted of a single base deletion, causing a frameshift, and the other was a G-to-A substitution in the consensus 5-prime splice donor site. Both mutations potentially generated null mutants. One of these mutations was found to segregate with the disease in the family, and the second appeared to be a de novo mutation.
In NPH1 patients who carried a hemizygous deletion at the NPHP1 region, Hildebrandt et al. (1997) detected additional point mutations in NPHP1 but not in the adjacent gene MALL.
Jiang et al. (2009) used Nphp1-mutant mice carrying an exon 20 deletion and transgenic mice expressing EmGFP-tagged nephrocystin to demonstrate that nephrocystin was localized to the connecting cilium axoneme, where it affected the sorting mechanism and transportation efficiency of the intraflagellar transport between inner and outer segments of photoreceptors.
Hildebrandt et al. (1997) performed SSCP for 18 of the 20 exons of the NPH1 gene in 6 multiplex and 6 simplex nephronophthisis-1 (NPHP1; 256100) families in which PCR was negative for a homozygous deletion in the 2q13 region. In 3 NPH1 families, hemizygous mutations were found, in which a heterozygous paternal deletion was combined with a heterozygous maternal point mutation. In 1 family the mother was heterozygous for a G-to-T transversion at position 1 of the splice donor consensus of exon 18 in the NPHP1 gene. The affected child was hemizygous for the transversion.
In the family of a child with nephronophthisis (NPHP1; 256100), Hildebrandt et al. (1997) found that the father was hemizygous for the wildtype sequence (carrying the deletion on the other chromosome), whereas the mother was heterozygous for deletion of G at position +1 of the canonical splice donor consensus sequence of exon 14 in the NPHP1 gene; the affected child was hemizygous for the single nucleotide deletion.
In a child with nephronophthisis (NPHP1; 256100), Hildebrandt et al. (1997) found hemizygosity for a nonsense mutation in the NPHP1 gene; a T-to-A transversion in exon 2 converted codon TTG (leu) to TAG (stop). The mother was heterozygous for this mutation.
In a child with nephronophthisis (NPHP1; 256100) associated with Cogan-type congenital ocular motor apraxia (COMA; 257550), Betz et al. (2000) identified hemizygosity for a G-to-A transition at nucleotide 1027 of the NPHP1 gene, leading to a gly343-to-arg substitution and an alteration of an 80% conserved splice donor consensus. The NPHP1 gene was deleted on the other allele. The mother and a healthy child were heterozygous for this point mutation.
Nephronophthisis 1
Approximately 80% of patients with nephronophthisis (NPHP1; 256100) demonstrate a homozygous deletion of about 290 kb that encompasses the NPHP1 gene (Konrad et al., 1996; Hildebrandt et al., 1997; Saunier et al., 2000).
Senior-Loken Syndrome 1
Caridi et al. (1998) described Senior-Loken syndrome (SLSN1; 266900), the association of nephronophthisis with autosomal recessive retinitis pigmentosa, in patients with homozygous deletion of the NPHP1 gene.
Joubert Syndrome 4
In 2 sibs with a mild form of Joubert syndrome (JBTS4; 609583), Parisi et al. (2004) demonstrated homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with nephronophthisis alone. A hallmark of that disorder is cerebellar vermis hypoplasia with prominent superior cerebellar peduncles, creating the 'molar tooth sign' (MTS) on axial MRI. Parisi et al. (2004) suggested that the MTS may be relatively common in patients with juvenile nephronophthisis without classic symptoms of JS.
In 4 patients with Joubert syndrome from 3 nonconsanguineous families, Parisi et al. (2006) identified homozygosity for deletion of the NPHP1 gene. The molar tooth sign in these patients had a distinctive appearance, with elongated but not thickened superior cerebellar peduncles.
Ala-Mello, S., Sankila, E.-M., Koskimies, O., de la Chapelle, A., Kaariainen, H. Molecular studies in Finnish patients with familial juvenile nephronophthisis exclude a founder effect and support a common mutation causing mechanism. J. Med. Genet. 35: 279-283, 1998. [PubMed: 9598719] [Full Text: https://doi.org/10.1136/jmg.35.4.279]
Benzing, T., Gerke, P., Hopker, K., Hildebrandt, F., Kim, E., Walz, G. Nephrocystin interacts with Pyk2, p130(Cas), and tensin and triggers phosphorylation of Pyk2. Proc. Nat. Acad. Sci. 98: 9784-9789, 2001. [PubMed: 11493697] [Full Text: https://doi.org/10.1073/pnas.171269898]
Betz, R., Rensing, C., Otto, E., Mincheva, A., Zehnder, D., Lichter, P., Hildebrandt, F. Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J. Pediat. 136: 828-831, 2000. [PubMed: 10839884]
Caridi, G., Murer, L., Bellantuono, R., Sorino, P., Caringella, D. A., Gusmano, R., Ghiggeri, G. M. Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am. J. Kidney Dis. 32: 1059-1062, 1998. [PubMed: 9856524] [Full Text: https://doi.org/10.1016/s0272-6386(98)70083-6]
Delous, M., Hellman, N. E., Gaude, H.-M., Silbermann, F., Le Bivic, A., Salomon, R., Antignac, C., Saunier, S. Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6. Hum. Molec. Genet. 18: 4711-4723, 2009. [PubMed: 19755384] [Full Text: https://doi.org/10.1093/hmg/ddp434]
Donaldson, J. C., Dempsey, P. J., Reddy, S., Bouton, A. H., Coffey, R. J., Hanks, S. K. Crk-associated substrate p130(Cas) interacts with nephrocystin and both proteins localize to cell-cell contacts of polarized epithelial cells. Exp. Cell Res. 256: 168-175, 2000. [PubMed: 10739664] [Full Text: https://doi.org/10.1006/excr.2000.4822]
Hildebrandt, F., Otto, E., Rensing, C., Nothwang, H. G., Vollmer, M., Adolphs, J., Hanusch, H., Brandis, M. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nature Genet. 17: 149-153, 1997. [PubMed: 9326933] [Full Text: https://doi.org/10.1038/ng1097-149]
Jiang, S.-T., Chiou, Y.-Y., Wang, E., Chien, Y.-L., Ho, H.-H., Tsai, F.-J., Lin, C.-Y., Tsai, S.-P., Li, H. Essential role of nephrocystin in photoreceptor intraflagellar transport in mouse. Hum. Molec. Genet. 18: 1566-1577, 2009. [PubMed: 19208653] [Full Text: https://doi.org/10.1093/hmg/ddp068]
Konrad, M., Saunier, S., Heidet, L., Silbermann, F., Benessy, F., Calado, J., Le Paslier, D., Broyer, M., Gubler, M.-C., Antignac, C. Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis. Hum. Molec. Genet. 5: 367-371, 1996. [PubMed: 8852662] [Full Text: https://doi.org/10.1093/hmg/5.3.367]
Mollet, G., Silbermann, F., Delous, M., Salomon, R., Antignac, C., Saunier, S. Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. Hum. Molec. Genet. 14: 645-656, 2005. [PubMed: 15661758] [Full Text: https://doi.org/10.1093/hmg/ddi061]
Parisi, M. A., Bennett, C. L., Eckert, M. L., Dobyns, W. B., Gleeson, J. G., Shaw, D. W. W., McDonald, R., Eddy, A., Chance, P. F., Glass, I. A. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am. J. Hum. Genet. 75: 82-91, 2004. [PubMed: 15138899] [Full Text: https://doi.org/10.1086/421846]
Parisi, M. A., Doherty, D., Eckert, M. L., Shaw, D. W. W., Ozyurek, H., Aysun, S., Giray, O., Al Swaid, A., Al Shahwan, S., Dohayan, N., Bakhsh, E., Indridason, O. S., Dobyns, W. B., Bennett, C. L., Chance, P. F., Glass, I. A. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J. Med. Genet. 43: 334-339, 2006. [PubMed: 16155189] [Full Text: https://doi.org/10.1136/jmg.2005.036608]
Saunier, S., Calado, J., Benessy, F., Silbermann, F., Heilig, R., Weissenbach, J., Antignac, C. Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis. Am. J. Hum. Genet. 66: 778-789, 2000. [PubMed: 10712196] [Full Text: https://doi.org/10.1086/302819]
Saunier, S., Calado, J., Heilig, R., Silbermann, F., Benessy, F., Morin, G., Konrad, M., Broyer, M., Gubler, M.-C., Weissenbach, J., Antignac, C. A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis. Hum. Molec. Genet. 6: 2317-2323, 1997. [PubMed: 9361039] [Full Text: https://doi.org/10.1093/hmg/6.13.2317]
Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell. Biol. 192: 1023-1041, 2011. [PubMed: 21422230] [Full Text: https://doi.org/10.1083/jcb.201012116]