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  1. Identification of monogenic variants in steroid-resistant and steroid-sensitive nephrotic syndrome
    Mansour B, Lemberg K, Schneider R, Saida K, Elmubarak I, Yu S, et al.
    Pediatr Nephrol, 2026 Jun;41(6):1663-1675.
    PMID: 41575523 DOI: 10.1007/s00467-026-07151-7
    BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) constitutes the second most common cause of chronic kidney disease (CKD) in children. A monogenic cause can be identified in approximately 25% of SRNS cases. In contrast, steroid-sensitive or steroid-dependent nephrotic syndrome (SSNS/SDNS) is typically attributed to multifactorial or immunological causes and rarely linked to monogenic etiology.

    METHODS: We performed exome sequencing (ES) in 237 families, including 183 with SRNS and 54 with SSNS/SDNS.

    RESULTS: A (likely) pathogenic variant in a known SRNS gene was identified in 29/183 individuals with SRNS (15.8%). Additionally, 6/183 (3.3%) individuals with SRNS carried pathogenic variants in phenocopy genes-genes associated with diseases that clinically mimic SRNS. The diagnostic yield was significantly higher in individuals with ≥ 50 Mb homozygosity-by-descent (HBD) (44.7% vs. 8.5%) and in those with SRNS disease onset before 1 year of age (41.9%). In individuals with SSNS/SDNS, we found a likely causative variant in only 1 of 54 probands.

    CONCLUSIONS: A genetic cause was established in 19.1% of SRNS patients (15.8% in known SRNS genes and 3.3% in phenocopy genes), but only 1.9% of non-steroid-resistant cases.

  2. Fulltext Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly
    Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, et al.
    Nat Genet, 2017 Oct;49(10):1529-1538.
    PMID: 28805828 DOI: 10.1038/ng.3933
    Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
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