The NPHS1 gene is located on chromosome 19 at 19q13.12 and encodes the protein nephrin, which forms the slit diaphragm between podocyte foot processes (the glomerular filtration barrier in the kidney).
NPHS1 was first reported in relation to autosomal recessive nephrotic syndrome type 1 in 1994 (Kestila et al., PMID: 8178817). The preferred disease name suggested for this disorder is ‘Nephrotic syndrome - NPHS1’. The mechanism of pathogenicity is known to be loss of function. The disorder is characterized by significant protein loss in the urine within the first weeks of life causing generalized edema.
At least 26 variants (frameshift, nonsense, splice, missense) have been reported in 71 probands in 4 publications (PMIDs: 8178817, 9660941, 9915943, 18503012 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data.
This gene-disease relationship is also supported by animal models, expression studies, in vitro functional assays, and rescue assays. In particular, nephrin knockout mice showed congenital nephrotic syndrome (PMID 11136707) which could be rescued using doxycycline-induced expression of rat nephrin (PMID 19948823), nephrin expression was demonstrated in normal kidneys but lost in patients with autosomal recessive frameshift or nonsense NPHS1 mutations (PMID 10972661), and in-vitro functional assays demonstrated a nonsense NPHS1 mutation stopped nephrin-mediated signalling of intracellular pathways AP-1 and MAPK (PMID 11562357), whilst certain missense NPHS1 mutations caused nephrin accumulation in the endoplasmic reticulum, preventing its expression at the cell surface (PMID 11726550). A total of 5.5/6 pts. for experimental evidence was reached
In summary, there is definitive evidence supporting the relationship between NPHS1 autosomal recessive nephrotic syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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