<i>LMNA</i>rs4641 and the Muscle Lamin A and C Isoforms in Twins—Metabolic Implications and Transcriptional Regulation

Wegner, Lise; Anthonsen, Stine; Bork-Jensen, Jette; Dalgaard, Louise Torp; Hansen, Torben; Pedersen, Oluf; Poulsen, Pernille; Vaag, Allan

doi:10.1210/jc.2009-2675

Cited by 10 publications

(12 citation statements)

References 24 publications

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“…This LMNA SNP is located in exon 10, at the physiological splice site of LMNA pre-mRNAs, whose use by the splicing machinery leads to the production of prelamin A rather than 'by default' lamin C-encoding mRNAs. This SNP was previously variably reported to influence [24][25][26] or not 27-29 the disease severity and lamin A/C expression levels. 20 We first checked the possibility in cis association of one of the SNP alleles with the LMNA mutations, and found none.…”

Section: Discussionmentioning

confidence: 85%

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

et al. 2015

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Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.

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Section: Discussionmentioning

confidence: 85%

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

et al. 2015

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“…In addition, Miranda et al (2008) observed altered lamin A to lamin C mRNA ratio in both obesity and type 2 diabetes. Noteworthy, insulin has been suggested to have an influence on lamin A to lamin C mRNA ratio (Wegner et al 2010). Acute insulin stimulation was shown to increase lamin A mRNA, whereas lamin C mRNA was decreased in skeletal muscle biopsies from young and elderly twins carrying a polymorphism in LMNA (Wegner et al 2010).…”

Section: Altered Lamin a To Lamin C Expression Ratio In Diseasesmentioning

confidence: 99%

“…Noteworthy, insulin has been suggested to have an influence on lamin A to lamin C mRNA ratio (Wegner et al 2010). Acute insulin stimulation was shown to increase lamin A mRNA, whereas lamin C mRNA was decreased in skeletal muscle biopsies from young and elderly twins carrying a polymorphism in LMNA (Wegner et al 2010). It is important to note that there is evidence that disruption of the balance between the major A-type lamin isoforms at the transcript or protein levels may lead to human diseases.…”

Section: Altered Lamin a To Lamin C Expression Ratio In Diseasesmentioning

confidence: 99%

Do lamin A and lamin C have unique roles?

Al-Saaidi

Bross

2014

Chromosoma

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The A-type lamins, lamin A and lamin C, generated from a single gene, LMNA, are major structural components of the nuclear lamina. The two alternative splice products have mostly been studied together because they have been considered to be interchangeable. However, several lines of evidence indicate that in spite of being generated from the same gene and having high similarities in their primary sequences, the two isoforms are not equivalent in different biological aspects in both health and disease. The key question is whether they have both overlapping and unique functions and whether they are distinctly regulated. Based on the so far available experimental evidence, lamin A appears to be the most regulated A-type isoform during development, aging, and disease which indicates that lamin A is implicated in many different biological aspects and may have a greater repertoire of specialized functions than lamin C. The aim of this review is to point out differences between the two major LMNA splice variants and the consequences of these differences on their functions. This may guide further research and be of prime importance for the understanding of the pathogenesis of LMNA mutations.

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“…The second condition could be a lamin A/C mutation or a multisystem metabolic defect with the myocardium being predominantly affected. Whether the LMNA polymorphism rs4641 (c.1698C>T; p.H566H) was responsible for the variable phenotype remains speculative, but previous studies have shown that this SNP is associated with an increased risk to develop diabetes [9,10]. Arguments for a metabolic defect are the combination of dCMP, thrombopenia, hypothyroidism, diverticulosis, liver hemangiomas, the double kidney and the repeatedly elevated serum lactate levels.…”

Section: Discussionmentioning

confidence: 99%

Dilated, Arrhythmogenic Cardiomyopathy in Emery-Dreifuss Muscular Dystrophy Due to the Emerin Splice-Site Mutation c.449 + 1G>A

Finsterer

Stöllberger²,

Sehnal³

et al. 2014

Cardiology

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Objective: Cardiac involvement in X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) usually includes arrhythmias but not dilative cardiomyopathy (dCMP). Here, we report an X-EDMD patient with severe dCMP and life-threatening ventricular arrhythmias associated with other phenotypic features unusual for X-EDMD. Case Report: A 46-year-old patient with X-EDMD due to the known splice-site mutation c.449 + 1G>A in the emerin gene experienced palpitations for the first time at the age of 21 years, and a first syncope at the age of 23 years. He was started on phenprocoumon due to atrial fibrillation and systolic dysfunction. At the age of 28 years he received his first pacemaker. Echocardiography at the age of 36 years showed left ventricular dilatation, enlarged atria, myocardial thickening, 28% ejection fraction and diastolic dysfunction. dCMP was suspected. At the age of 38 years, a cardiac resynchronization therapy system was implanted, which was upgraded to an implantable cardioverter defibrillator (ICD) because of ventricular tachycardias (at the age of 42 years). During the following months, the ICD discharged 30 times due to ventricular tachycardias. In May 2013, he required recurrent cardio-pulmonary resuscitation because ventricular fibrillation occurred with no discharge of the ICD. He was listed for heart transplantation. He also had hypothyroidism, liver hemangiomas, thrombopenia, anemia and diverticulosis. Conclusions: X-EDMD may occur along with dCMP. An ICD may be ineffective for ventricular fibrillation in X-EDMD. X-EDMD may be associated with unusual, atypical phenotypic features.

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LMNArs4641 and the Muscle Lamin A and C Isoforms in Twins—Metabolic Implications and Transcriptional Regulation

Cited by 10 publications

References 24 publications

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

Do lamin A and lamin C have unique roles?

Dilated, Arrhythmogenic Cardiomyopathy in Emery-Dreifuss Muscular Dystrophy Due to the Emerin Splice-Site Mutation c.449 + 1G>A

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