The risk of nephrotic range proteinuria and kidney failure in primary laminopathies is genotype specific.

BACKGROUNDPrimary laminopathies are a heterogeneous group of rare diseases caused by nuclear lamina dysfunction due to pathogenic LMNA variants. However, despite their ubiquitous expression, LMNA variants have rarely been linked to chronic kidney disease (CKD). Here, we systematically investigate clinical implications and functional underpinnings of a distinct LMNA missense variant [lamin A/C p.(Arg349Trp)] that has sporadically been found in patients with a complex phenotype including lipodystrophy, proteinuria, and focal segmental glomerulosclerosis (FSGS).METHODSIn clinical and functional terms, we compare lamin A/C Arg349Trp with missense changes at Arg482, the most common hotspot residue for type 2 familial partial lipodystrophy (FPLD2). In particular, we assess renal endpoints in corresponding patient cohorts and investigate disease-associated alterations in vitro.RESULTSIn contrast to patients with FPLD2, individuals with lamin A/C Arg349Trp experience high-grade proteinuria and a rapid decline of glomerular filtration rate with kidney failure at a median age of 43 years. Mechanistically, we demonstrate that Arg349Trp associates with an abrogation of the structural interaction between lamin A/C and nucleoporin 155, nuclear pore complex aggregation, and an alteration of TGF-β1-dependent signaling.CONCLUSIONWhile patients with Lamin A/C Arg482 missense changes are at very low risk for progressive CKD, patients harboring Arg349Trp show nephrotic range proteinuria and kidney failure in midlife. Hence, high-grade proteinuric kidney disease is genotype specific, and patients with the Arg349Trp substitution require early renoprotective intervention to potentially halt progression and prevent kidney failure.FUNDINGGerman Research Foundation, project IDs 502928386, 508310822, 539950728, 445703531, 451693578, 471294925, 496611648, and 539950728; Else Kröner-Fresenius Foundation (2019_A96).