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.
Sebastian Sewerin, Charlotte Aurnhammer, Mohamed Hamed et al.· JCI Insight· 0 citations
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by de novo LMNA mutations. Patients develop severe systemic symptoms limiting life quality and ultimately causing death from cardiovascular events. Despite extensive research, treatment options remain limited. Here, we investigated the role of long non-coding RNAs (lncRNAs) in the development of vascular pathology in HGPS. We analyzed an available single-cell RNA sequencing dataset from aortic arch cells of wild-type and LmnaG609G/G609G mice aged 6, 10 and 12 weeks. Several lncRNAs implicated in cardiovascular disease, such as Carmn, Dancr, Gas5, Kcnq1ot1, Meg3, Neat1, Pvt1, or Trp53cor1, were dysregulated in LmnaG609G/G609G vascular smooth muscle cells (VSMCs). This dysregulation was most pronounced in disease-enriched VSMCs, which showed severe dysfunction with disease progression. Furthermore, lncRNA changes were dynamic over time. Transcription factor motif enrichment analysis identified putative regulatory links between dysregulated lncRNAs, and cellular programs associated with VSMC stress responses and phenotypic switching. In contrast, LmnaG609G/G609G fibroblasts displayed a distinct lncRNA expression profile, including H19, Gas5, Kcnq1ot1, and Pvt1, associated with fibrosis and inflammation. Together, our findings reveal progressive, and cell type-specific lncRNA dysregulation in the HGPS vasculature and highlight lncRNAs as candidates for exploring new therapeutic strategies.
Lara G. Merino, Santhilal Subhash, D. Whisenant et al.· GeroScience· 0 citations
The premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by de novo LMNA mutations producing the aberrant Lamin A isoform progerin. HGPS patients die from cardiovascular disease, with their arteries showing extensive cellular and structural remodeling, but the mechanisms driving vascular dysfunction are not fully understood. To define molecular processes underlying progressive vascular degeneration in HGPS, we performed single-cell RNA-sequencing (scRNA-seq) of aortic arch cells from LmnaG609G/G609G mice without atheroprone stimuli. These mice carry the murine equivalent of the most common HGPS-causing mutation and faithfully recapitulate the vascular phenotype. Sequencing was performed at multiple ages to capture disease-related and time-dependent transcriptional changes. We used Smart-seq2 for sequencing, due to its high sensitivity and full-length transcript coverage. Histology, immunostaining and in situ hybridization were used for arterial characterization. The aortic arch of LmnaG609G/G609G mice exhibited a gradual age-dependent vascular smooth muscle cell (VSMC) loss, accompanied by a transient proliferation surge, and ultimately by increased apoptosis. scRNA-seq identified transcriptionally distinct cell populations with unique features that evolved during disease progression. Disease-enriched VSMCs at early stages were characterized by elevated endoplasmic reticulum (ER) stress. With disease development, these VSMCs further underwent phenotypic switching toward a fibroblast-like state, which was predicted to expand through non-cell-autonomous mechanisms. At later stages, disease-enriched VSMCs upregulated apoptotic gene expression, partially coinciding with sustained ER stress. Furthermore, progeria VSMCs showed an increase in both DNA damage and somatic SNVs, with the increased number of SNVs correlating with high expression of ER stress, ROS and p53-related genes. In contrast, progeria-enriched fibroblasts either became activated or increased their cartilage production and showed a delayed accumulation of somatic SNVs compared to VSMCs, highlighting both a cell-type-specific progerin response and differences in somatic mutation susceptibility. Our study shows that progerin leads to somatic mutation accumulation particularly in VSMCs, highlighting the need for early, cell-type-specific therapeutic intervention in HGPS to prevent permanent vascular tissue damage. In addition, the cell-type-specific molecular dynamics of the aortic arch VSMCs and fibroblasts during HGPS disease progression are provided in a user-friendly searchable scRNA-seq database available for preclinical research targeting vascular aging.
Lara G. Merino, Gwladys Revêchon, Santhilal Subhash et al.· Genome Medicine· 1 citation
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