lmna gene
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2021 ◽  
Vol 79 (12) ◽  
pp. 1368-1371
Author(s):  
Agnieszka Zienciuk-Krajka ◽  
Magdalena Chmara ◽  
Monika Lica-Gorzynska ◽  
Karolina Dorniak ◽  
Joanna Kwiatkowska ◽  
...  

2021 ◽  
Vol 10 (21) ◽  
pp. 5075
Author(s):  
Valentina Ferradini ◽  
Joseph Cosma ◽  
Fabiana Romeo ◽  
Claudia De Masi ◽  
Michela Murdocca ◽  
...  

Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. Mutations in LMNA gene, encoding for lamin A/C, account for 10% of familial DCM. LMNA-related cardiomyopathies are characterized by heterogeneous clinical manifestations that vary from a predominantly structural heart disease, mainly mild-to-moderate left ventricular (LV) dilatation associated or not with conduction system abnormalities, to highly pro-arrhythmic profiles where sudden cardiac death (SCD) occurs as the first manifestation of disease in an apparently normal heart. In the present study, we select, among 77 DCM families referred to our center for genetic counselling and molecular screening, 15 patient heterozygotes for LMNA variants. Segregation analysis in the relatives evidences other eight heterozygous patients. A genotype–phenotype correlation has been performed for symptomatic subjects. Lastly, we perform in vitro functional characterization of two novel LMNA variants using dermal fibroblasts obtained from three heterozygous patients, evidencing significant differences in terms of lamin expression and nuclear morphology. Due to the high risk of SCD that characterizes patients with lamin A/C cardiomyopathy, genetic testing for LMNA gene variants is highly recommended when there is suspicion of laminopathy.


2021 ◽  
Vol 10 (21) ◽  
pp. 4834
Author(s):  
Louise Benarroch ◽  
Enzo Cohen ◽  
Antonio Atalaia ◽  
Rabah Ben Yaou ◽  
Gisèle Bonne ◽  
...  

Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.


2021 ◽  
Vol 56 ◽  
pp. 102530
Author(s):  
Ji-Zhen Lu ◽  
Zhi-Bin Qiao ◽  
Lu Zhang ◽  
Hong-Xia Cao ◽  
Zhi-Hui Bai ◽  
...  
Keyword(s):  

2021 ◽  
Vol 22 (15) ◽  
pp. 7874
Author(s):  
Yuval Shemer ◽  
Lucy N. Mekies ◽  
Ronen Ben Jehuda ◽  
Polina Baskin ◽  
Rita Shulman ◽  
...  

LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients’ induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (If) density; (2) prolonged action potential duration and increased L-type Ca2+ current (ICa,L) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na+/Ca2+ exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A271-A271
Author(s):  
Maria Cristina Foss de Freitas ◽  
Baris Akinci ◽  
Callie Corsa ◽  
Amy E Rothberg ◽  
Ormond A MacDougald ◽  
...  

Abstract Phenotypic heterogeneity is well known in Familial Partial Lipodystrophy Type 2 (FPLD2), a rare form of adipose tissue disorder caused by pathogenic mutations in LMNA gene. Animal studies from our group have identified an association between adipose tissue loss and an increase in bone mineral density (BMD) in a mouse model with adipose tissue specific knockout of LMNA gene. Aiming to translate this observation to patients with FPLD2, we analyzed body composition data obtained by dual X-ray absorptiometry from 61 patients diagnosed with FPLD2 and 61 individuals with no diagnosis of FPLD (nFPLD) matched for sex, age and body mass index. As expected, we observed lower total fat mass in FPLD2 patients compared to nFPLD (15.8±9.3 kg vs. 28.5±12.4 kg, p=0.001), as well as lower fat mass in regions of arms, legs and trunk. Interestingly, patients with FPLD2 showed lower bone mineral density (BMD) compared to nFPLD 1.0±0.2 g/cm3 vs 1.2±0.1 g/cm3, p=0.01) and lower t-score (0.2±1.8 vs.1.5±1.2). We then aimed to determine if the patients with FPLD2 displayed differences with respect to genotype. For these analyses, the FPLD2 group was divided according to the pathogenic variant; 42 with mutations on the hot spot codon of the LMNA gene (R482: 50.2 ± 164.8 years, 76% women) and 19 with non-hot spot codon mutations (nR482: 44.8 ± 12.8 years, 78% women). Patients in the R482 group were older when they were first diagnosed with lipodystrophy (39.6 ± 18.6 years vs. 36.5 ± 12.3 years, p=0.05). Also, nR482 group presented with more progeroid characteristics. Patients in n-R482 group also had lower weight compared to R482 and nFPLD groups (64.4±14.4 vs. 73.3±18.5 and 77.6±16.6 kg, p=0.01), as well as lower total fat mass (15.3±5.1 vs. 15.8±9.3 and 25.7±11.4 kg, p=0.01) and fat mass ratio (5.8±1.9 vs. 5.9±3.1 and 9.0±4.1, p= 0.01). Control group bone mass was significantly higher in arms, legs and trunk compared to the R482 and nR482 groups. Moreover, the R482 group had lower bone mass in the legs compared to nR482 (690.5±227.2 vs.703.5±95.3 g, p=0.01), while showing higher trunk bone mass (676.4±266.7 vs. 674.1±79.3, p=0.04), in addition to greater fat mass in the legs (3.3±1.6 vs. 2.6±0.7 kg, p=0.05) and trunk areas (10.3±6.1 vs. 10.0±4.2 kg, p=0.03). There were no differences in total bone mass, BMD, and t-scores, according to genotype. Our data showed more fat preservation in LMNA R482 than nR482, presumably leading to a later lipodystrophy diagnosis. Furthermore, bone mass in different regions may be affected by LMNA genotype; however, more studies are needed to define the bone phenotype and fracture risk in FPLD2 population fully.


2021 ◽  
Vol 10 (7) ◽  
pp. 1497
Author(s):  
David Araújo-Vilar ◽  
Antía Fernández-Pombo ◽  
Berta Victoria-Martínez ◽  
Adrián Mosquera-Orgueira ◽  
Silvia Cobelo-Gómez ◽  
...  

Type 2 familial partial lipodystrophy, or Dunnigan disease, is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution. This rare condition results from variants principally affecting exons 8 and 11 of the LMNA gene. In this study, five FPLD2-diagnosed patients carrying the c.1583C>T, p.(Thr528Met) variant in exon 9 of the LMNA gene and with obvious clinical heterogeneity were evaluated. Specific polymorphisms in LMNA and in PPARG were also detected. Exhaustive clinical course, physical examination, biochemical features and family history were recorded, along with the assessment of anthropometric features and body composition by dual-energy X-ray absorptiometry. Preadipocytes obtained from a T528M patient were treated with the classic adipose differentiation medium with pioglitazone. Various adipogenes were evaluated by real-time PCR, and immunofluorescence was used to study intracellular localization of emerin, lamin A and its precursors. As demonstrated with Oil red O staining, the preadipocytes of the T528M patient failed to differentiate, the expression of various adipogenic genes was reduced in the lipodystrophic patient and immunofluorescence studies showed an accumulation of farnesylated prelamin A in T528M cells. We conclude that the T528M variant in LMNA could lead to FPLD2, as the adipogenic machinery is compromised.


2021 ◽  
Vol 10 (6) ◽  
pp. 1259
Author(s):  
David Araújo-Vilar ◽  
Sofía Sánchez-Iglesias ◽  
Ana I. Castro ◽  
Silvia Cobelo-Gómez ◽  
Álvaro Hermida-Ameijeiras ◽  
...  

Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the “atypical” disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56–1937] vs. 130.0 [55–505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene.


2021 ◽  
Vol 21 ◽  
Author(s):  
Md. Mominur Rahman ◽  
Kazi Sayma Ferdous ◽  
Muniruddin Ahmed ◽  
Mohammad Touhidul Islam ◽  
Md. Robin Khan ◽  
...  

: Lamin A/C encoded by LMNA gene is an important component for the maintenance of the nuclear structure. Mutation in the lamin A/C leads to a group of inherited disorders is known as laminopathies. In the human body, there are several mutations in the LMNA gene have been identified. It can affect diverse organs or tissues or can be systemic, causing different diseases. In this review, we mainly focused on one of the most severe laminopathies, Hutchinson-Gilford progeria syndrome (HGPS). HGPS is an immensely uncommon, deadly, metameric ill-timed laminopathies caused by the abnormal splicing of the LMNA gene and production of an aberrant protein known as progerin. Here, we also presented the currently available data on the molecular mechanism, pathophysiology, available treatment, and future approaches of this deadly disease. Due to the production of progerin an abnormal protein leads to an abnormality in nuclear structure, defects in DNA repair, shortening of telomere, impairment in gene regulation which ultimately results in aging in the early stage of life. Now some treatment options are available for this disease but a proper understanding of the molecular mechanism of this disease will help to develop a more appropriate treatment which makes it an emerging area of research.


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