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

BACKGROUND: Primary 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). METHODS: In 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. RESULTS: In contrast to FPLD2 patients, 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. CONCLUSIONS: While 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. FUNDING: German Research Foundation, project IDs 502928386, 445703531, and grants HA 9779/2-1, HA 6908/4-1, HA 6908/7-1, HA 6908/8-1, HA 6908/12-1.

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Publication Details

Journal
JCI Insight
Published
2026-07-16
DOI
https://doi.org/10.1172/jci.insight.192062
Primary Topic
Nuclear Structure and Function
Type
article
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article

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

Theodoros Georgomanolis, Martin Heni, Yves Reznik, Elena Vorona et al.
JCI Insight
Nuclear Structure and Function
article

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

Theodoros Georgomanolis, Martin Heni, Yves Reznik, Elena Vorona, Barış Akıncı, Carsten Bergmann, Wolfram Antonin, Marie‐Christine Vantyghem, Sebastian Sewerin, Alessandra Gambineri, Giovanni Ceccarini, Gwladys Revêchon, Iztok Štotl, Christin Findeisen, Charlotte Aurnhammer, Jan Halbritter, J. Roume, Konstanze Miehle, Mohamed Hamed, Maria Eriksson, Julia von Schnurbein, Éva Csajbók, Thomas Scherer, Marek Kollár, Camille Vatier, Šárka Tesařová, Constantin A. Wolff, Martin Wabitsch, David Araujo-Vilar, Ekaterina Sorkina, Ria Schönauer, Corinne Vigouroux
article en

Abstract

BACKGROUND: Primary 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). METHODS: In 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. RESULTS: In contrast to FPLD2 patients, 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. CONCLUSIONS: While 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. FUNDING: German Research Foundation, project IDs 502928386, 445703531, and grants HA 9779/2-1, HA 6908/4-1, HA 6908/7-1, HA 6908/8-1, HA 6908/12-1.

JCI Insight
University of Pisa (IT), Inserm (FR), University of Cologne (DE), Dokuz Eylül University (TR), Universität Ulm (DE), Charles University (CZ), University of Szeged (HU), Université de Lille (FR), Ljubljana University Medical Centre (SI), Karolinska Institutet (SE), Sorbonne Université (FR), Endocrinology Research Center (RU), Lille’s Cardiology Hospital (FR), Hôpital Saint-Antoine (FR), University Hospital Münster (DE), Centre Hospitalier Intercommunal de Poissy (FR), Center for Research in Molecular Medicine and Chronic Diseases (ES), Institute of Clinical and Experimental Medicine (CZ), University Hospital Ulm (DE), General University Hospital in Prague (CZ), Medical University of Vienna (AT), Charité - Universitätsmedizin Berlin (DE), RWTH Aachen University (DE), Leipzig University (DE), University of Bologna (IT), Université de Caen Normandie (FR)
Deutsche Forschungsgemeinschaft, RWTH Aachen University
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Nuclear Structure and Function
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