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NPHS2
NPHS2 stomatin family member, podocin
The NPHS2 gene provides instructions for producing podocin, a critical protein located in the kidneys that is essential for proper blood filtration. NPHS2 plays a vital role in kidney function, particularly within specialised structures called glomeruli.
NPHS2 is located on the long (q) arm of chromosome 1, at band 1q25.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The NPHS2 gene encodes a protein called podocin, which is primarily found in the kidneys. This protein is crucial for the function of podocytes, specialised cells within the kidney's filtering units called glomeruli. Podocin contributes to the formation and integrity of the slit diaphragm, a structure that acts as a filtration barrier to prevent proteins from escaping the blood into urine.
Pathogenic variants in the NPHS2 gene are frequently associated with inherited forms of nephrotic syndrome, which can lead to kidney failure.
What the gene does
The NPHS2 gene directs the synthesis of podocin, a protein vital for kidney health and function. Podocin is located within the podocytes, which are kidney cells integral to the filtration process occurring in the glomeruli. Specifically, podocin is concentrated at the slit diaphragm, a highly selective barrier positioned between adjacent podocytes.
This slit diaphragm functions to retain essential proteins within the bloodstream while allowing waste products and smaller molecules to be excreted in urine. Podocin is thought to facilitate the assembly and localisation of other essential proteins to the podocyte cell surface, which are necessary for the slit diaphragm's integrity. Furthermore, podocin is involved in cell signalling pathways, helping podocytes adapt and respond to changes encountered during the kidney's filtration activities.
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Chromosome location
The NPHS2 gene is situated on chromosome 1, specifically at position 1q25.2. This genomic location refers to the long (q) arm of chromosome 1, within region 2, band 5, and sub-band 2.
Protein structure
The NPHS2 gene encodes a protein composed of 383 amino acids. Analysis of its structure reveals specific regions with distinct characteristics. The N-terminal end of the protein contains a disordered region spanning amino acids 1-76. Another disordered region is found towards the C-terminal end, encompassing amino acids 355-383.
Key variants
Variants in the NPHS2 gene can alter the structure or function of the podocin protein. These genetic changes can impair the kidney's filtration system, leading to various health conditions. The impact of a specific variant depends on its nature and location within the 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.130G>T | p.Glu44Ter | Pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.293_294del | p.Leu98fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.2T>C | p.Met1Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.370T>C | p.Cys124Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.378+1_378+2delinsTG | - | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.451+3A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.483del | p.Tyr162fs | Pathogenic/Likely pathogenic | ★★☆☆ | Steroid-resistant nephrotic syndrome |
c.62_63insG | p.His21fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.705_713del | p.Leu236_Arg238del | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 2 |
c.738+1del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Steroid-resistant nephrotic syndrome |
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 NPHS2 gene are primarily associated with different forms of nephrotic syndrome, a kidney disorder characterised by excessive protein leakage into the urine. This condition can manifest early in life as congenital nephrotic syndrome, which typically progresses to kidney failure in early childhood. Other forms, such as infantile nephrotic syndrome, may present later with similar but often less severe symptoms.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic NPHS2 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
The NPHS2 gene is included in several UK NHS national genomic testing panels. It is part of the 'DDG2P' panel, the 'Proteinuric renal disease' panel (R195), and the 'Unexplained kidney failure in young people' panel. Its presence on these panels indicates its recognised clinical significance within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the NPHS2 gene responsible for?
The NPHS2 gene provides instructions for making podocin, a protein crucial for the filtering function of the kidneys. Podocin helps form a barrier that prevents essential proteins from leaving the blood and entering the urine.
What conditions are associated with NPHS2 gene variants?
Variants in the NPHS2 gene are primarily associated with various types of nephrotic syndrome, a kidney disorder. This can include congenital nephrotic syndrome, which starts in infancy, and other forms that may appear later in childhood.
How is NPHS2 relevant to kidney health?
NPHS2 is highly relevant to kidney health because its protein product, podocin, is essential for the integrity of the kidney's filtration system. Proper podocin function ensures that the kidneys can effectively filter waste products while retaining vital proteins in the body.
References
- Wang JJ, Mao JH. The etiology of congenital nephrotic syndrome: current status and challenges. World journal of pediatrics : WJP. 2016. PMID: 26961288
- Sadowski CE, Lovric S, Ashraf S. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. Journal of the American Society of Nephrology : JASN. 2015. PMID: 25349199
- Grahammer F, Schell C, Huber TB. The podocyte slit diaphragm--from a thin grey line to a complex signalling hub. Nature reviews. Nephrology. 2013. PMID: 23999399
- Machuca E, Benoit G, Nevo F. Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. Journal of the American Society of Nephrology : JASN. 2010. PMID: 20507940