NPHS1 gene mutations confirm congenital nephrotic syndrome in four Brazilian cases: A novel mutation is described

Abstract

Despite the small size of the cohort, this study contributed to the increasing number of deleterious mutations in the NPHS1 gene by describing a new mutation. Also, since we identified NPHS1 pathogenic mutations as the cause of the disease in all cases analyzed, it might be a frequent cause of CNS in the South Eastern region of Brazil, although the analysis of a larger sample is required to obtain more indicative epidemiological data.

Characterization of a novel disease-associated mutation within NPHS1 and its effects on nephrin phosphorylation and signaling

“…As NPHS1 mutations in Y1176, Y1193 or Y1217 have not been directly implicated in instances of human disease, a significant role for nephrin tyrosine phosphorylation in the pathogenesis of CNS has been largely overlooked. Hundreds of NPHS1 mutations have now been annotated in CNS patients [ 4 ], particularly within hot-spots in the extracellular Ig-like motifs or their linker regions. However, not all mutations cause retention of nephrin in the ER of cultured cells, despite their classification as pathogenic using protein folding prediction algorithms, and their impact on nephrin tyrosine phosphorylation remains to be determined [ 38 ].…”

“…Defined as the Fin major mutation, this prototypic nonsense mutation in the nephrin ectodomain results in a complete loss of nephrin protein. Since this time, more than 250 different nonsense, frameshift, splice-site or missense mutations have been annotated for NPHS1 in the Human Gene Mutation Database ( http://www.hgmd.cf.ac.uk ), and they are distributed across all exons [ 4 ]. Mutations have been classified as mild or severe, according to predicted effects on nephrin protein expression [ 5 , 6 ], and they variably impact the age of onset and disease progression [ 7 ].…”

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

“…Mouse knockout models have clearly demonstrated that loss of either nephrin ( 34 , 35 ), podocin ( 36 ), or neph1 ( 37 ) expression is sufficient to disrupt SD formation and induce severe disease within days of birth and even in utero . Furthermore, over 250 distinct genetic mutations in NPHS1 ( 38 ) and over 100 in NPHS2 ( 39 ) have been identified to date. The overall importance of nephrin–podocin communication in development is further highlighted in instances of congenital nephrotic syndrome (CNS) in which single mutations in either NPHS1 or NPHS2 are benign in respective parents, but their digenic heterozygosity leads to congenital disease ( 40 ), a relatively uncommon phenomenon ( 41 ).…”

Brazilian Network of Pediatric Nephrotic Syndrome (REBRASNI)

“…4 Outside the cell, RNLS acts as a potent pro-survival signal when it binds to its cell membrane receptor, the plasma membrane calcium adenosine triphosphatase isoform PMCA4, and activates a variety of intracellular signaling pathways including the protein kinase B (AKT), extracellularsignal-regulated kinase (ERK), and signal transducer and activator of transcription 3 (STAT3) pathways. [5][6][7] Administration of RNLS minimizes injury in in vivo models of myocardial infarction, 8 ischemic tubular necrosis, 9 and acute pancreatitis. S1 Conversely, RNLS deficiency in RNLS knockout mice exacerbates cisplatin-mediated acute and chronic renal injury, which is reversed by administration of RNLS.…”