Lamin A/C mutations in dilated cardiomyopathy

Tesson, Frédérique; Saj, Michal; Uvaize, Musfira Mohamed; Nicolas, Hannah; Płoski, Rafał; Bilińska, Zofia T.

doi:10.5603/cj.a2014.0037

Cited by 60 publications

(58 citation statements)

References 90 publications

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“…Because individual-level phenotypic data is unavailable for the ExAC cohort, we were unable to determine whether these variants correlated with myocardial disease or other specific phenotypes. However, since there is already strong evidence that LMNA mutations contribute to heart disease in the general population (Parks et al, 2008; Tesson et al, 2014), these variants are of particular interest for functional follow-up.…”

Section: Resultsmentioning

confidence: 99%

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

et al. 2017

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Mutations in LMNA, encoding nuclear intermediate filament proteins lamins A and C, cause multiple diseases (‘laminopathies’) including muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy (FPLD2), insulin resistance syndrome and progeria. To assess the prevalence of LMNA missense mutations (‘variants’) in a broad, ethnically diverse population, we compared missense alleles found among 60,706 unrelated individuals in the ExAC cohort to those identified in 1,404 individuals in the laminopathy database (UMD-LMNA). We identified 169 variants in the ExAC cohort, of which 37 (∼22%) are disease-associated including p.I299V (allele frequency 0.0402%), p.G602S (allele frequency 0.0262%) and p.R644C (allele frequency 0.124%), suggesting certain LMNA mutations are more common than previously recognized. Independent analysis of LMNA variants via the type 2 diabetes (T2D) Knowledge Portal showed that variant p.G602S associated significantly with type 2 diabetes (p = 0.02; odds ratio = 4.58), and was more frequent in African Americans (allele frequency 0.297%). The FPLD2-associated variant I299V was most prevalent in Latinos (allele frequency 0.347%). The ExAC cohort also revealed 132 novel LMNA missense variants including p.K108E (limited to individuals with psychiatric disease; predicted to perturb coil-1B), p.R397C and p.R427C (predicted to perturb filament biogenesis), p.G638R and p.N660D (predicted to perturb prelamin A processing), and numerous Ig-fold variants predicted to perturb phenotypically characteristic protein–protein interactions. Overall, this two-pronged strategy— mining a large database for missense variants in a single gene (LMNA), coupled to knowledge about the structure, biogenesis and functions of A-type lamins— revealed an unexpected number of LMNA variants, including novel variants predicted to perturb lamin assembly or function. Interestingly, this study also correlated novel variant p.K108E with psychiatric disease, identified known variant p.I299V as a potential risk factor for metabolic disease in Latinos, linked variant p.G602 with type 2 diabetes, and identified p.G602S as a predictor of diabetes risk in African Americans.

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Section: Resultsmentioning

confidence: 99%

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

et al. 2017

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“…In view of the fact that this specific LMNA mutation has been associated with dilated cardiomyopathy (10), the patient underwent a transthoracic echocardiography and electrocardiography, which did not reveal any pathological findings.…”

Section: Investigationmentioning

confidence: 99%

Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T LMNA mutation

Fountas¹,

Giotaki²,

Dounousi

et al. 2017

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the LMNA gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non-specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin-converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense LMNA mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.Learning points:Lipodystrophy is a rare disorder characterized by the complete or partial loss of subcutaneous adipose tissue, insulin resistance, diabetes mellitus and hyperlipidemia.Proteinuric renal disease is a prevalent feature of generalized lipodystrophy but rare in familial partial lipodystrophy.Patients carrying the c.1045C > T missense LMNA mutation (p.R349W) may present with familial partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy.

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“…51 A history of premature atrial fibrillation, conduction diseases, pacemaker and/or defibrillator implantation suggests the presence of genetic causes such as laminopathies, desminopathies and some dystrophinopathies. 52,53 In this case the pattern of inheritance could be helpful. 54 Many genetic causes have also manifestations in other organ systems: for example, a familial history of neuromuscular disease and a personal history of diabetes and sensorineural deafness could suggest mitochondriopathies.…”

Section: Dilated Phenotypementioning

confidence: 99%

“…52 An acute AV block presentation may suggest myocarditis, while a chronic stable form suggests cardiac sarcoidosis or genetic causes (laminopathies, desminopathies, myotonic dystrophy). A premature paroxysmal AF may be a manifestation of SCN5A mutation, 59 laminopathies 53 or polygenic disorder.…”

Section: Dilated Phenotypementioning

confidence: 99%

Diagnosis of Cardiomyopathies: Tips and Tricks for Internists and General Practitioners

2017

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Cardiomyopathies are little known to internists and general practitioners (GPs), and not always able to arouse the interest of cardiologists. Probably, this happens because cardiomyopathies are perceived as rare and complex disorders, a prerogative of a few dedicated centers. This may partly explain why the diagnosis of cardiomyopathy is often missed and, consequently, why cardiomyopathies are largely underdiagnosed. Internists and general practitioners should have an interest in these conditions, because cardiomyopathies are not as rare as generally perceived, and because their complexity can be unravelled with knowledge and methodology. Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal in the absence of coronary artery disease or abnormal loading conditions. Irrespective of the cardiac imaging technique used, a limited number of phenotypes are defined based on ventricular morphology and function. These basic phenotypes include hypertrophic, dilated, restrictive and right ventricular arrhythmogenic cardiomyopathies. Aim of this review is to describe a simplified approach to the detection of the underlying causes of specific phenotypes. We will focus our attention on the basic phenotypes, presenting a diagnostic work-up and a suggestive clinical case for each phenotype.

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Lamin A/C mutations in dilated cardiomyopathy

Abstract: Dilated cardiomyopathy (DCM) is one of the leading causes of heart (Cardiol J 2014; 21, 4: 331-342)

Cited by 60 publications

References 90 publications

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes

Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T LMNA mutation

Diagnosis of Cardiomyopathies: Tips and Tricks for Internists and General Practitioners

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