NPHP1
protein-codingnephrocystin 1, the group of NPHP complex
Gene summary
This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
- NPH1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~82.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015229
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009728
Submitter: ClinGen
The relationship between NPHP1 (nephrocystin) and Nephronophthisis was evaluated using the ClinGen Clinical Validity Framework on 27 January 2021. Nephronophthisis is an autosomal recessively inherited disease characterised by renal failure, with onset under the age of 30. Affected children develop polyuria and polydipsia, and growth retardation with an inactive urinary sediment. Their kidneys are small or normal-sized and hyperechoic with corticomedullary cysts and tubular basement membrane abnormalities. Nephronophthisis 1 (MIM:256100) is the commonest inherited cause of kidney failure in children and affects one in 50,000 (Waldherr 1982, PMID:7072145). About 20% affected individuals have extrarenal features such as retinitis pigmentosa (Senior Loken syndrome, MIM:266900), or cerebellar vermis hypoplasia and other multiorgan abnormalities (Joubert syndrome, MIM:609583). (Simms 2009, PMID:21660307). Other extra-renal features include liver fibrosis, gaze palsies, situs inversus and skeletal defects. In addition, at least 20 different genes are affected in nephronophthisis, and variants in NPHP1 account for 20% of all cases. Each of the affected proteins has a slightly different function but is involved in ciliary function. LUMPING and SPLITTING: Using the criteria of the ClinGen Lumping and Splitting Working Group, there are assertions for different disease entities (nephronophthisis, Senior-Loken syndrome, Joubert syndrome) for NPHP1 mutations, but there was a consistent inheritance pattern of AR, and the disease mechanism for all these conditions was a loss of function. Therefore, all of the disease entities have been lumped into one disease entity. The gene for nephronophthisis 1 was mapped to chromosome 2p13 in a cohort of 18 multiplex families with nephronophthisis resulting in a LOD score of 4.78 at theta = 0.05 in 1993 (Antignac 1993, PMID:7981755). Subsequently, individuals were demonstrated with a homozygous large deletion about 250 kb with a 100 kb inverted duplication involving both the NPHP1 and BENE (MALL) genes (Saunier 1997, PMID:9361039). A 4.8 kb band was absent on Southern blotting consistent with a homozygous deletion of NPHP1 (Konrad 1996, PMID:8852662), and 60-80% of affected individuals have at least a single copy of this deletion (Saunier 1997, PMID:9361039). Deletions are not due to a founder effect but rather occur because of the flanking low copy number repetitive sequences that potentially enable a stem-loop structure on the DNA strand and homologous recombination (Saunier 2000, PMID:10712196). The disease mechanism is loss of function. There are more than 200 reports of homozygous deletions (Hildebrandt 2001, PMID:11168925; Otto 2006, PMID:18076122; Halbritter 2013, PMID:23559409). There are also numerous compound heterozygous variants due to a null variant plus a second variant including missense variants (Caridi 2006, PMID:16762963; Otto 2006, PMID:18076122; Halbritter 2013, PMID:23559409) as well as case reports. A case control study of 5605 adults with end-stage kidney failure from 12 countries were compared with a control population matched for ethnicity. Twenty-six (0.5%) of those with kidney failure had homozygous deletions but none of 3311 normal kidney donors (OR= 31.45 (1.91 to 516.36, p=0.01)) (Snoek 2018, PMID:29654215). Genetic evidence reached the maximum score (12 points). This gene-disease relationship is also supported by the function of the gene product nephrocystin 1. There is no correlation between variant type and extrarenal features. Thus, there is no variant type or location that predominates in any of Senior-Loken or Joubert syndrome. NPHP1 appears to be located in the ciliary axoneme, in the transition zone and in the microtubular organising centre within the cell. Its precise function is not known but it is probably a scaffolding protein involved in cell-cell adhesion, that is able to recruit signalling molecules into specialized protein complexes (Mollet 2005, PMID:15661758). It interacts with the products of many other NPHP genes, located in the primary cilium, including NPHP4 and RPGRIP1L at the transition zone, that link it with inversin (NPHP2) (Mollet 2005, PMID:15661758); and p130cas, Tensin, Filamin and Focal adhesion kinase 2 all involved in cell-cell adhesion and cell signalling as demonstrated with coimmunoprecipitation and by yeast two hybrid screens (Donaldson 2002, PMID:12006559; 2000 PMID:10739664). NPHP1 colocalises with PALS1, PATJ and Par6 which are involved in tight function formation (Delous 2009, PMID:19755384). It is important in the Wnt and Shh signalling pathways. Nephrocystin is mainly expressed in the ureteric epithelial cells and tubular precursors in the kidney (Lindstrom 2018, PMID:29449453), and localizes to the transition zone at the ciliary base (Fliegauf 2006, PMID:16885411). Expression is abnormal in tracheal cells from patients with nephronophthisis, and patient-derived cells have some subtle abnormalities of ciliary motility (Fliegauf 2006, PMID:16885411). A mouse knockout has no kidney phenotype but has retinal and sperm abnormalities (Mouse Genome Informatics, PMID:30407599; Jiang 2008, PMID:18684731; Devi 2015, PMID:26198798). Zebrafish, in a combination of nphp1 and nphp4 morpholinos, have increased kidney cysts (Slanchev 2011, PMID:21596840). Likewise in C elegans disruption of both nphp1 and nphp4 compromise ciliary structure (Yee 2015, PMID: 26540106). In a non-patient derived cell culture model, shRNA-knockdown of NPHP1 results in abnormal cilia formation and can be rescued with re-expression of human NPHP1 (Delous 2009, PMID:19755384). Likewise CRISPR-Cas 9 induced NPHP1 deletion in NIH 3T3 cells results in fewer ciliated cells that are rescued by re-expression of plasmid Nphp1 (Wiegering 2018, PMID:29650680). Thus the score for experimental evidence for a gene-disease association was also the maximum (6 points). Both the clinical evidence and experimental evidence have been upheld and replicated over time. The only reservations about the experimental data were the facts that the function of NPHP1 was not precisely known and it had no functional assay for its measurement. In addition all the models were complicated and often required a mutation in a second gene (such as nphp4) in addition to nphp1, to develop the typical cystic phenotype. In summary, the clinical validity classification of DEFINITIVE for the relationship between NPHP1 and Nephronophthisis 1 was approved by the Cystic Kidney disease GCEP on 27 January 2021 using the Gene Clinical Validity Standard Operating Procedure (SOP) version 8.
Inheritance Pattern: AR
Disease ID:MONDO:0009728
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009728
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012308
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012308
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0005308
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0017842
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009728
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009728
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012308
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Hematologic; Neurologic; Ophthalmologic; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: The conditions may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial; Renal transplant has been described, though nephrotic syndrome may recur post-transplantation
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NPHP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001128178.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 10 | 203 | 1 | 214 | ||
| missense | 1 | 3 | 357 | 24 | 385 | |
| nonsense | 12 | 25 | 37 | |||
| start loss | 2 | 1 | 3 | |||
| frameshift | 37 | 25 | 1 | 63 | ||
| splice donor/acceptor (+/-2bp) | 8 | 30 | 6 | 44 | ||
| Total | 58 | 85 | 375 | 227 | 1 | 746 |
Highest pathogenic variant AF is 0.0001869066
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001121650.1 | 20 | MANE Select | |
| Ensembl | ENSP00000389879.3 | 20 | MANE Select | |
| RefSeq | NP_000263.2 | 20 | Standard | |
| RefSeq | NP_001121651.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nphp1 | Danio rerio | Structure: pronephric proximal convoluted tubule Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Anchoring of the basal body to the plasma membrane
- Cilium Assembly
- Organelle biogenesis and maintenance
Biological Process
- signal transduction
- excretion
- visual behavior
- cell projection organization
- actin cytoskeleton organization
Molecular Function
- structural molecule activity
- protein binding
Cellular Component
- cytosol
- cytoskeleton
- cell-cell junction
- adherens junction
- bicellular tight junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000316534
- Coding exons
- 20
- Length
- 82756
- Individuals with no LoFs
- 125668
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 79
- Defined
- 125747
- p
- 0.000314
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.226 | 369 | 381 | 0.967 | 0.0000192 | 4814 |
| Missense (PolyPhen) | 127 | 143.75 | 0.88347 | 1953 | ||
| Synonymous | 0.777 | 124 | 136 | 0.915 | 0.00000727 | 1365 |
| Loss of Function | 1.69 | 33 | 45.2 | 0.729 | 0.00000216 | 533 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00080 | 0.00080 | rare |
| Latino/Admixed American | 0.00046 | 0.00046 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.00019 | 0.00018 | rare |
| European (Non-Finnish) | 0.00024 | 0.00024 | rare |
| South Asian | 0.00027 | 0.00026 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Together with BCAR1 it may play a role in the control of epithelial cell polarity. Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8 (By similarity). Does not seem to be strictly required for ciliogenesis (By similarity). Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling. May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development. In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Nephronophthisis 1 (NPHP1) [MIM:256100]: An autosomal recessive inherited disease characterized by anemia, polyuria, polydipsia, isosthenuria and death in uremia. Symmetrical destruction of the kidneys involving both tubules and glomeruli occurs. The underlying pathology is a chronic tubulo-interstitial nephropathy with characteristic tubular basement membrane thickening and medullary cyst formation. Associations with extrarenal symptoms, especially ocular lesions, are frequent. The age at death ranges from about 4 to 15 years. {ECO:0000269|PubMed:10839884}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Senior-Loken syndrome 1 (SLSN1) [MIM:266900]: A renal- retinal disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. {ECO:0000269|PubMed:9856524}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 4 (JBTS4) [MIM:609583]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. Joubert syndrome type 4 is a phenotypically mild form. {ECO:0000269|PubMed:15138899, ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.178
Intolerance Scores
- LoFtool
- 0.993
- RVIS EVS
- 0.07
- RVIS percentile EVS
- 58.96
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.541
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |