Abstract
Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-β2) levels significantly discriminated Musc-LMNA from controls; interleukin-1β (IL-1β), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.
Highlights
The lamin A and C proteins, produced through the alternative splicing of the LMNA gene on chromosome 1, are type V intermediate filaments located in the nuclear lamina, beneath the inner nuclear membrane [1,2,3]
The quantification of the serum concentration of 27 inflammatory cytokines showed a significant increase in the levels of IL-1b (p = 0.0024), IL-1 receptor antagonist (IL-1ra) (p = 0.0066), IL-4 (p = 0.0314), IL-17 (p < 0.0001), granulocyte colony-stimulating factor (G-CSF)
The serum levels of IL-1β, IL-1ra, IL-4, IL-17, G-CSF and TGF-β2 were significantly higher in the Musc-LMNA patients compared to healthy controls, whereas IL-7 and IL-5 concentrations were significantly lower in the Musc-LMNA patients than in controls
Summary
The lamin A and C proteins, produced through the alternative splicing of the LMNA gene on chromosome 1, are type V intermediate filaments located in the nuclear lamina, beneath the inner nuclear membrane [1,2,3]. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation of the LMNA gene make the diagnostic process difficult for laminopathies [5], and classical genetic screens appear to have limited predictive value for disease development. Clinical outcome measures have been poorly investigated in muscular laminopathies (Musc-LMNA) and natural history has not been elucidated yet. The availability of objectively measurable, obtainable and reproducible circulating biomarkers would be an extremely useful tool to help differentiate and stratify disease subgroups, which would aid in the evaluation of disease progression in clinical practice and in pharmacological clinical trials; circulating biomarkers may represent possible therapeutic targets in Musc-LMNA. A complex proteomic analysis of plasma samples derived from LMNA-mutated patients identified several proteins, mainly cytokines, related to inflammatory response and homeostasis maintenance [6]
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