Laminopathies belong to the group of diseases caused by mutations in genes encoding nuclear envelope proteins, referred to as nuclear envelopathies (Maraldi et al., 2005). Whilst disease-causing mutations in all other envelopathies involve EMD, LBR, MAN1, LAP2 and AAAS genes, laminopathies are caused by mutations in the LMNA gene, coding for lamin A/C (primary laminopathies) or the FACE-1 gene, affecting the posttranslational processing of prelamin A (secondary laminopathies). More than 200 different mutations have been identified in the LMNA gene of the laminopathic individuals screened so far. The variety of diseased phenotypes in primary laminopathies (16 have been since now described) is impressive; in fact, they fall into five classes. In three of them specific tissues are mainly affected, i.e.: skeletal and/or cardiac muscles; peripheral nerves; adipose tissue. In the other classes, several tissues are affected, either presenting systemic alterations typical of premature aging, or overlapping phenotypes with the coexistence of two or more tissue involvements (Broers et al., 2006). Whilst LMNA mutations leading to striated muscle laminopathies are spread all along the gene, mutations are mostly restricted to quite specific codons in lipodystrophic laminopathies, as well as in two premature aging syndromes, the mandibuloacral dysplasia and the Hutchinson-Gilford progeria (Broers et al., 2006). Relations between phenotypic alterations and genotypes have been not particularly significant (Hegele, 2005), so that different pathogenic mechanisms have been proposed to account for the different classes of laminopathies, which are based on the variety of functions played by lamins (Maraldi et al., 2006b). The expected role of lamins is to maintain the structural integrity of the nucleus; therefore, attention has been focused on the consequence of mutations affecting the process of lamin assembly on the physical integrity of nuclei and cells exposed to mechanical strain. Typical features of mechanical damage have been reported in muscular laminopathies, consisting in herniations or holes in the nuclear envelope. Mutations of lamin A/C, which occur both at the rod domain and at the Ig-like fold, could affect lamin higher order assembly, as well as interactions of lamins with proteins associated with the inner nuclear membrane (Krimm et al., 2002; Strelkov et al., 2004). The gene expression hypothesis has been advanced to account for the pathophysiology of laminopathies with a main involvement of adipose tissue, such as familial partial lipodystrophy, but also mandibuloacral dysplasia and atypical Werner syndrome, in which lipodystrophy is part of complex diseased phenotypes (Cohen et al., 2001). In these cases, a percentage of nuclei of the affected tissues has been found to accumulate prelamin A at the nuclear envelope. This resulted in a reduced availability of SREBP1, sequestered at the nuclear envelope; this, in turn, reduced the activation of PPARγ, which is essential for adipocyte differentiation (Capanni et al., 2005). A further pathogenic mechanism, referred to as cell proliferation theory (Gotzmann and Foisner, 2005), is based on the assumption that lamin interaction with pRb is crucial for cell differentiation and regeneration (Markiewicz et al., 2002; Mariappan and Parnaik, 2005; Dorner et al., 2006). Therefore, LMNA mutations could affect the capacity for regeneration of adult stem cells, preventing their amplification (Mounkes et al., 2003). In the present study we provide experimental evidence in agreement with the hypothesis that accumulation of unprocessed lamin A into the nucleus exerts a toxic effect which results in premature aging of different tissues (Pendas et al., 2002).

Prelamin A processing and heterochromatin dynamics in laminopathies

MARALDI, NADIR;MANZOLI, FRANCESCO ANTONIO
2007

Abstract

Laminopathies belong to the group of diseases caused by mutations in genes encoding nuclear envelope proteins, referred to as nuclear envelopathies (Maraldi et al., 2005). Whilst disease-causing mutations in all other envelopathies involve EMD, LBR, MAN1, LAP2 and AAAS genes, laminopathies are caused by mutations in the LMNA gene, coding for lamin A/C (primary laminopathies) or the FACE-1 gene, affecting the posttranslational processing of prelamin A (secondary laminopathies). More than 200 different mutations have been identified in the LMNA gene of the laminopathic individuals screened so far. The variety of diseased phenotypes in primary laminopathies (16 have been since now described) is impressive; in fact, they fall into five classes. In three of them specific tissues are mainly affected, i.e.: skeletal and/or cardiac muscles; peripheral nerves; adipose tissue. In the other classes, several tissues are affected, either presenting systemic alterations typical of premature aging, or overlapping phenotypes with the coexistence of two or more tissue involvements (Broers et al., 2006). Whilst LMNA mutations leading to striated muscle laminopathies are spread all along the gene, mutations are mostly restricted to quite specific codons in lipodystrophic laminopathies, as well as in two premature aging syndromes, the mandibuloacral dysplasia and the Hutchinson-Gilford progeria (Broers et al., 2006). Relations between phenotypic alterations and genotypes have been not particularly significant (Hegele, 2005), so that different pathogenic mechanisms have been proposed to account for the different classes of laminopathies, which are based on the variety of functions played by lamins (Maraldi et al., 2006b). The expected role of lamins is to maintain the structural integrity of the nucleus; therefore, attention has been focused on the consequence of mutations affecting the process of lamin assembly on the physical integrity of nuclei and cells exposed to mechanical strain. Typical features of mechanical damage have been reported in muscular laminopathies, consisting in herniations or holes in the nuclear envelope. Mutations of lamin A/C, which occur both at the rod domain and at the Ig-like fold, could affect lamin higher order assembly, as well as interactions of lamins with proteins associated with the inner nuclear membrane (Krimm et al., 2002; Strelkov et al., 2004). The gene expression hypothesis has been advanced to account for the pathophysiology of laminopathies with a main involvement of adipose tissue, such as familial partial lipodystrophy, but also mandibuloacral dysplasia and atypical Werner syndrome, in which lipodystrophy is part of complex diseased phenotypes (Cohen et al., 2001). In these cases, a percentage of nuclei of the affected tissues has been found to accumulate prelamin A at the nuclear envelope. This resulted in a reduced availability of SREBP1, sequestered at the nuclear envelope; this, in turn, reduced the activation of PPARγ, which is essential for adipocyte differentiation (Capanni et al., 2005). A further pathogenic mechanism, referred to as cell proliferation theory (Gotzmann and Foisner, 2005), is based on the assumption that lamin interaction with pRb is crucial for cell differentiation and regeneration (Markiewicz et al., 2002; Mariappan and Parnaik, 2005; Dorner et al., 2006). Therefore, LMNA mutations could affect the capacity for regeneration of adult stem cells, preventing their amplification (Mounkes et al., 2003). In the present study we provide experimental evidence in agreement with the hypothesis that accumulation of unprocessed lamin A into the nucleus exerts a toxic effect which results in premature aging of different tissues (Pendas et al., 2002).
N.M. Maraldi; E. Mattioli; G. Lattanzi; M. Columbaro; C. Capanni; D. Camozzi;S. Squarzoni; F. A. Manzoli
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/42769
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