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NPHP1
nephrocystin 1
The NPHP1 gene provides instructions for the nephrocystin-1 protein, which is essential for the proper function of cilia, microscopic structures involved in cell signalling. The NPHP1 gene is crucial for producing the nephrocystin-1 protein.
NPHP1 is located on the long (q) arm of chromosome 2, at band 2q13. Arm ratio per GRCh38 - banding schematic.
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Overview
The NPHP1 gene, also known as nephrocystin 1, provides the genetic blueprint for a protein called nephrocystin-1. This protein is primarily involved in the intricate workings of cilia, which are tiny projections extending from the outer membrane of cells. Cilia are critical for various cellular processes, including signalling pathways that transmit information within and between cells, influencing the development and function of numerous tissues and organs within the body.
Dysfunction of the nephrocystin-1 protein due to variants in the NPHP1 gene is linked to a group of disorders known as ciliopathies, particularly those affecting the kidneys and eyes.
What the gene does
The nephrocystin-1 protein, encoded by the NPHP1 gene, is thought to be involved in maintaining the structural integrity and proper function of cilia. These cellular organelles are crucial for development and cell-to-cell communication. Nephrocystin-1 is typically located at the base of cilia in various cell types, including those found in the kidneys, respiratory tract, and the light-sensitive retina of the eye. While its precise function is still being elucidated, nephrocystin-1 is believed to interact with other proteins, forming part of a larger complex that supports normal ciliary activity. These interactions are vital for the signalling pathways that cilia mediate, which are essential for cellular homeostasis.
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Chromosome location
The NPHP1 gene is located on chromosome 2, specifically at position 2q13. This chromosomal address indicates its position on the long arm (q) of chromosome 2, within region 13. The gene spans a significant segment of the genome and directs the synthesis of a protein composed of 732 amino acids.
Protein structure
The nephrocystin-1 protein consists of 732 amino acids and exhibits a modular structure with several identifiable domains. It contains two coiled coil domains, one located at amino acids 3-105 and another at amino acids 127-150. There are also two disordered regions, found at amino acids 103-153 and 205-244. Additionally, a key SH3 domain is present at amino acids 152-212, which is often involved in protein-protein interactions.
Key variants
Genetic variations within the NPHP1 gene can impact the production or function of the nephrocystin-1 protein. These changes, known as pathogenic variants, can disrupt the protein's role in cilia, leading to a range of associated health conditions. The most common type of variant associated with NPHP1-related disorders is a large deletion that removes the entire gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1270-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.127C>T | p.Gln43Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome with renal defect |
c.182del | p.Asn61fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis 1 |
c.1897_1906del | p.Thr633fs | Pathogenic/Likely pathogenic | ★★☆☆ | NPHP1-related disorder |
c.385_386del | p.Ser129fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.69+1del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome with renal defect |
c.735del | p.His247fs | Pathogenic | ★★☆☆ | Nephronophthisis 1 |
c.771+124C>T | Q299* | Pathogenic/Likely pathogenic | ★★☆☆ | Nephronophthisis |
c.771+58C>T | R277* | Pathogenic/Likely pathogenic | ★★☆☆ | NPHP1-related disorder |
c.84_87del | p.Ser29fs | Pathogenic | ★★☆☆ | NPHP1-related disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the NPHP1 gene are primarily associated with nephronophthisis, a kidney disorder. At least 23 variants have been identified as causing nephronophthisis type 1, which accounts for approximately 20% of cases. NPHP1 variants are also implicated in Joubert syndrome, a complex neurological disorder, and Senior-Loken syndrome, which combines features of nephronophthisis with retinal degeneration. These conditions are typically inherited in an autosomal recessive manner.
- Nephronophthisis
- Joubert syndrome (NPHP1) Dedicated page coming soon
- Senior-Loken syndrome Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic NPHP1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the NPHP1 gene is included on several NHS Genomic Medicine Service clinical panels, indicating its recognised clinical significance. It is classified as 'green' for conditions such as Cystic kidney disease, Renal ciliopathies, and Tubulointerstitial kidney disease (R202). NPHP1 is also assessed on panels for Foetal anomalies (R21), Retinal disorders (R32), and Rare multisystem ciliopathy disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the NPHP1 gene?
The NPHP1 gene provides instructions for making the nephrocystin-1 protein. This protein is important for the normal structure and function of cilia, which are microscopic, finger-like projections on cell surfaces involved in cell signalling and development.
What conditions are associated with NPHP1 gene variants?
Variants in the NPHP1 gene are associated with several conditions, including nephronophthisis, a kidney disorder; Joubert syndrome, which primarily affects neurological development; and Senior-Loken syndrome, characterised by both kidney disease and retinal degeneration.
How is NPHP1-related disease inherited?
Conditions linked to NPHP1 gene variants are typically inherited in an autosomal recessive manner. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition.
References
- Lindstrand A, Davis EE, Carvalho CM. Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome. American journal of human genetics. 2014. PMID: 24746959
- Ronquillo CC, Bernstein PS, Baehr W. Senior-Løken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis. Vision research. 2012. PMID: 22819833
- Hurd TW, Hildebrandt F. Mechanisms of nephronophthisis and related ciliopathies. Nephron. Experimental nephrology. 2011. PMID: 21071979
- Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. Journal of the American Society of Nephrology : JASN. 2007. PMID: 17513324
- Fliegauf M, Horvath J, von Schnakenburg C. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. Journal of the American Society of Nephrology : JASN. 2006. PMID: 16885411
- Parisi MA, Bennett CL, Eckert ML. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. American journal of human genetics. 2004. PMID: 15138899
- Saunier S, Calado J, Benessy F. Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis. American journal of human genetics. 2000. PMID: 10712196
- Hildebrandt F, Otto E, Rensing C. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nature genetics. 1997. PMID: 9326933