Prelamin A-mediated recruitment of SUN1 to the nuclear envelope directs nuclear positioning in human muscle

Mattioli, Elisabetta; Columbaro, Marta; Capanni, Cristina; Maraldi, Nadir M.; Cenni, Vittoria; Scotlandi, Katia; Marino, Maria Teresa; Merlini, Luciano; Squarzoni, Stefano; Lattanzi, Giovanna

doi:10.1038/cdd.2010.183

Cited by 73 publications

(148 citation statements)

References 58 publications

(90 reference statements)

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“…HEK293 were cultured in D‐MEM plus 10% fetal bovine serum. Skin fibroblasts expressing P4R LMNA from atypical progeria syndrome (APS) (Garg et al, 2009), R527H LMNA from mandibuloacral dysplasia (MADA) (Novelli et al, 2002), G608G LMNA from HGPS (De Sandre Giovannoli et al, 2003; Eriksson et al, 2003; Pellegrini et al, 2015), and cells from Emery‐Dreifuss muscular dystrophy (EDMD2) expressing Y259D mutated LMNA (Mattioli et al, 2011) or control fibroblasts were included in this study (Table 1). …”

Section: Methodsmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Section: Methodsmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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“…Lamin A/C was labeled using anti-lamin A/C polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA; Sc-6215), which was applied for 1 h at room temperature. 15 Bound antibody was detected with a horseradish peroxidase-conjugated anti-goat Ig, using diaminobenzidine as a substrate. Samples were counterstained with hematoxylin.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

et al. 2013

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Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/ TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM. With the exception of TTN, truncating mutations of which have been found in up to 27% of individuals with DCM, 1 a single DCM-causing gene accounts for no more than 6-8% of all cases. The known DCM disease genes include those encoding for proteins of the sarcomere, the Z-disk, the cytoskeleton, the mitochondria, RNA binding proteins, the sarcoplasmic reticulum, and the nuclear envelope. 2-4 Familial DCM exhibits a remarkable degree of clinical variability with respect to severity, penetrance, and age of onset. 5 Like familial hypertrophic cardiomyopathy (HCM), familial DCM is often characterized by incomplete penetrance, a high degree of variable expressivity even among

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“…The connection with extranuclear signal transducers is ensured by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, a protein chain including integral proteins of the inner and outer nuclear membrane, such as SUN1/2 and nesprin1/2 (encoded by SYNE1/2 genes), attached to lamins on the nuclear side and to actin and other cytoskeleton constituents on the cytoplasmic side. LINC proteins are reduced [12,13] or even mutated [13,14] in patients affected by cardiolaminopathies. The proven effect of LINC disorganization and reduced interplay between LINC components and lamins in laminopathic muscle cells is defective myonuclear positioning [12,14], which is a cause of altered muscle cell functionality [14].…”

Section: Pathogenetic Pathways In Cardiolaminopathiesmentioning

confidence: 99%

“…LINC proteins are reduced [12,13] or even mutated [13,14] in patients affected by cardiolaminopathies. The proven effect of LINC disorganization and reduced interplay between LINC components and lamins in laminopathic muscle cells is defective myonuclear positioning [12,14], which is a cause of altered muscle cell functionality [14]. These findings point to altered mechanosignalling transduction as a further pathogenetic event leading to heart dysfunction in laminopathies.…”

Section: Pathogenetic Pathways In Cardiolaminopathiesmentioning

confidence: 99%

“…In this context, elevated TGFbeta 2 and Akt/mTOR activation could also be the cause of reduced lamin A and prelamin A levels [15,17] at the cardiomyocyte nuclear envelope, a condition that favors LINC disorganization [12]. In agreement with this pathogenetic hypothesis, Erk 1/2 activation has been demonstrated in the presence of pathogenetic LMNA and SYNE1 mutations [7,13], and altered positioning of muscle nuclei has been demonstrated in LMNA, SYNE1 and SUN1 -linked Emery-Dreifuss muscular dystrophy with cardiomyopathy [12–14,18]. …”

Section: Pathogenetic Pathways In Cardiolaminopathiesmentioning

confidence: 99%

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Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Boriani

Biagini

Ziacchi

et al. 2018

Nucleus

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Lamin A/C gene mutations can be associated with cardiac diseases, usually referred to as ‘cardiolaminopathies’ characterized by arrhythmic disorders and/or left ventricular or biventricular dysfunction up to an overt picture of heart failure. The phenotypic cardiac manifestations of laminopathies are frequently mixed in complex clinical patterns and specifically may include bradyarrhythmias (sinus node disease or atrioventricular blocks), atrial arrhythmias (atrial fibrillation, atrial flutter, atrial standstill), ventricular tachyarrhythmias and heart failure of variable degrees of severity. Family history, physical examination, laboratory findings (specifically serum creatine phosphokinase values) and ECG findings are often important ‘red flags’ in diagnosing a ‘cardiolaminopathy’. Sudden arrhythmic death, thromboembolic events or stroke and severe heart failure requiring heart transplantation are the most dramatic complications of the evolution of cardiolaminopathies and appropriate risk stratification is clinically needed combined with clinical follow-up. Treatment with cardiac electrical implantable devices is indicated in case of bradyarrhythmias (implant of a device with pacemaker functions), risk of life-threatening ventricular tachyarrhythmias (implant of an ICD) or in case of heart failure with wide QRS interval (implant of a device for cardiac resynchronization). New technologies introduced in the last 5 years can help physicians to reduce device-related complications, thanks to the extension of device longevity and availability of leadless pacemakers or defibrillators, to be implanted in appropriately selected patients. An improved knowledge of the complex pathophysiological pathways involved in cardiolaminopathies and in the determinants of their progression to more severe forms will help to improve clinical management and to better target pharmacological and non-pharmacological treatments.

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Prelamin A-mediated recruitment of SUN1 to the nuclear envelope directs nuclear positioning in human muscle

Cited by 73 publications

References 58 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

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