A novel phenotypic expression associated with a new mutation in <i>LMNA</i> gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy

Araújo‐Vilar, David; Lado-Abeal, Joaquín; Palos-Paz, Fernando; Lattanzi, Giovanna; Bandín, Manuel A.; Bellido, Diego; Domínguez-Gerpe, Lourdes; Calvo, Carlos; Pérez, Oscar Mauricio; Рамазанова, А. Р.; Martínez-Sánchez, Noelia; Victoria, Berta; Costa-Freitas, Ana Teresa

doi:10.1111/j.1365-2265.2007.03146.x

Cited by 42 publications

(28 citation statements)

References 45 publications

(121 reference statements)

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“…FPLD, characterized by loss of fat tissue from the extremities, excess fat accumulation on the face and neck, and insulin-resistant diabetes, is prevailingly due to mutations located to exon 8; hypertrophic cardiomyopathy and aortic stenosis have been also reported in FPLD patients (Araujo-Vilar et al, 2008). The C-terminal domain of the lamin A, where mutations causing FPLD are clustered, binds specifically to SREBP1 (Lloyd et al, 2002).…”

Section: Laminopathies and Lamin-associated Cell Signaling Pathwaysmentioning

confidence: 98%

A‐type lamins and signaling: The PI 3‐kinase/Akt pathway moves forward

Marmiroli

Bertacchini

Beretti

et al. 2009

Journal Cellular Physiology

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Lamin A/C is a nuclear lamina constituent mutated in a number of human inherited disorders collectively referred to as laminopathies. The occurrence and significance of lamin A/C interplay with signaling molecules is an old question, suggested by pioneer studies performed in vitro. However, this relevant question has remained substantially unanswered, until data obtained in cellular and organismal models of laminopathies have indicated two main aspects of lamin A function. The first aspect is that lamins establish functional interactions with different protein platforms, the second aspect is that lamin A/C activity and altered function may elicit different effects in different cells and tissue types and even in different districts of the same tissue. Both these observations strongly suggest that signaling mechanisms targeting lamin A/C or its binding partners may regulate such a plastic behavior. A number of very recent data show involvement of kinases, as Akt and Erk, or phosphatases, as PP1 and PP2, in lamin A-linked cellular mechanisms. Moreover, altered activation of signaling in laminopathies and rescue of the pathological phenotype in animal models by inhibitors of signaling pathways, strongly suggest that signaling effectors related to lamin A/C may be implicated in the pathogenesis of laminopathies and may represent targets of therapeutic intervention. In face of such an open perspective of basic and applied research, we review current evidence of lamin A/C interplay with signaling molecules, with particular emphasis on the lamin A-Akt interaction and on the biological significance of their relationship.

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Section: Laminopathies and Lamin-associated Cell Signaling Pathwaysmentioning

confidence: 98%

A‐type lamins and signaling: The PI 3‐kinase/Akt pathway moves forward

Marmiroli

Bertacchini

Beretti

et al. 2009

Journal Cellular Physiology

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“…For example, the coexistence of EDMD2, CMD1A, and LGMD1B has been recognized within a family [27]. Moreover, some patients have been reported to carry features of more than one laminopathy phenotype, such as FPLD2 with cardiac involvement [28] or mandibuloacral dysplasia with myopathy [29]. These findings suggest that laminopathies are a complex group of multisystem disorders, whose phenotypes cannot be always considered as discrete entities, but rather show wide overlap, some individuals and families having features of several different laminopathies and some mutations causing diverse manifestations in different individuals [30].…”

Section: Short Story Of Diseases Related To the Nuclear Laminamentioning

confidence: 97%

“…These cases include: phenotypes combining clinical features of lipodystrophy presenting also variable combinations of skeletal and/or cardiac muscle alterations [28,64,65]; CMT2 axonal neuropathy phenotypes associated with myopathic features and cardiac disease [50]; phenotypes combining axonal neuropathy, partial lipodystrophy, and scapuloperoneal myopathy [51]; phenotypes combining early-onset myopathy and progeria [66]; phenotypes combining MAD and myopathy [29].…”

Section: Overlapping Phenotypesmentioning

confidence: 98%

Laminopathies

Maraldi¹,

Lattanzi²

2012

Cytoskeleton and Human Disease

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The laminopathies are a group of rare diseases characterized by a vast range of phenotypic alterations, due to mutations in lamin A and C or other nuclear envelope proteins. A-type lamins, as well as B-type lamins, belong to the type V intermediate filaments and, by polymerization, form the nuclear lamina, a component of the nuclear envelope. Following a brief description of the complex interactions between lamins and proteins of the nuclear membrane, this Chapter describes disease phenotypes that characterize each laminopathy, the possible mechanisms involved into the pathogenesis, as well as potential therapies based on the use of existing drugs. IntroductionFor many years, the nuclear lamina has been considered a structural component of the nuclear envelope (NE, [1]) and has been studied by cell biologists working on the description of the different phases of mitosis [2]. After the discovery that mutations in the genes encoding A-type lamins and associated NE proteins cause an impressive range of human diseases [3], new and unexpected functions have been attributed to lamins and the interest in the nuclear lamina has been greatly enhanced. Here, a description of the nuclear lamina intermediate filament network and of laminlinked diseases known as "laminopathies" will be provided. Although a detailed description of the NE is outside the scope of this Chapter, a brief overview of the general organization of this nuclear domain, with references to recent reviews on the subject will be presented in order to help the comprehension of disease mechanisms.As schematically indicated in Fig. 18.1, in the NE the outer and inner nuclear membranes ONM and INM) are not equivalent; in fact, the ONM is continuous N. M. Maraldi ( )

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“…Strikingly, in this patient, once hypercortisolism was cured, an abnormal fat distribution became more evident, although it was not as severe as observed in classical Dunnigan disease. This change in fat distribution was particularly intriguing because it highlighted important differences among LMNA mutations that cause FPLD (13). The R545H variant, previously associated with FPLD (7), caused severe metabolic syndrome with android fat distribution in this patient.…”

Section: Inflammatory Myopathy and Laminopathymentioning

confidence: 98%

“…Moreover, several patients with mutations outside the immunoglobulin-like fold of lamin A have lacked the typical FPLD2 phenotype but experienced insulin resistance (4). In addition, some cases of FPLD2 have been associated with heart conduction disorders, valvulopathies, and cardiomyopathy (12)(13)(14). Other authors have reported LMNA-associated complex phenotypes, including heart failure and limb-girdle muscular dystrophy, due to a Ser334del variant (15,16); muscular dystrophy, lipodystrophy, and cardiac rhythm disturbances related to a R527P variant (17); or FPLD, early heart failure, first-degree atrioventricular block, and late proximal muscle weakness due to a R28W variant (12).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory myopathy in the context of an unusual overlapping laminopathy

Guillín-Amarelle¹,

Sánchez-Iglesias²,

Varela³

et al. 2018

Archives of Endocrinology and Metabolism

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Summary Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery–Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot–Marie–Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff–Parkinson– White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA . This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA -associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

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A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy

Abstract: This patient shows a novel clinical form of FPLD2, due to a mutation affecting lamin A only, with cardiac involvement.

Cited by 42 publications

References 45 publications

A‐type lamins and signaling: The PI 3‐kinase/Akt pathway moves forward

A‐type lamins and signaling: The PI 3‐kinase/Akt pathway moves forward

Laminopathies

Inflammatory myopathy in the context of an unusual overlapping laminopathy

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