Senescent Cells as Drivers of Age-Related Diseases
Shamim I. Ahmad in Aging: Exploring a Complex Phenomenon, 2017
The nuclear envelope is lined by the nuclear lamina, a dense fibrillary network which provides mechanical support and regulates size, shape, and stability of the nucleus [85,86]. Nuclear lamina also partakes in a number of other functions including regulation of DNA synthesis, RNA transcription, and chromatin organization [87]. In mammals, the lamina contains major structural proteins categorized as type A (lamin A and C) and type B (lamin B1 and B2) lamins based on their isoelectric points [85]. Nuclear lamins are dynamic structures that are assembled and disassembled throughout the cell cycle. Lamin A and C are derived from the gene LMNA by alternative splicing and are expressed by non-proliferating and differentiated cells. Lamin B1 and B2 are encoded by separate genes LMNB1 and LMNB2 respectively and are strongly expressed by dividing and undifferentiated cells [88–90]. While there are two types of lamin B, expression of one or the other is sufficient for cell survival [86,91]. Expression of type A and B lamins are differentially regulated in specific tissues during embryogenesis [91,92].
Dilated Cardiomyopathy
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
Although the genetic analysis of DCM is important because it allows for early diagnosis in family members, it has less of an impact for the patients themselves, as examples of “genetic treatment” are still few and not widely accessible. The current exceptions concern patients who carry the LMNA gene mutation:Class IIa indication by international guidelines for ICD implantation early during follow-up, in the presence of certain additional risk factors and independently of LV disfunction severity.24A new molecule, ARRY-797, is currently being tested in a phase III clinical trial, after showing promising results in phase II. The small molecule acts by inhibiting the p38-MAPK pathway, which appears to be up-regulated in the deficit of LMNA.
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Mary N. Sheppard in Practical Cardiovascular Pathology, 2022
DCM may also occur in mitochondrial cytopathies and inherited metabolic disorders (e.g. haemochromatosis). Neuromuscular disease may accompany DCM, and in some forms of neuromuscular disease, the presenting feature may be cardiac. LMNA mutations can present with or without muscle disease, and the muscle disease ranges from limb-girdle muscular dystrophy to Emery-Dreifuss muscular dystrophy. In LMNA- and SCN5A-mediated cardiomyopathies, arrhythmias including atrial fibrillation or ventricular arrhythmias may be the presenting finding. Both X-linked and autosomal neuromuscular diseases can present with cardiomyopathy, and this includes Duchenne muscular dystrophy, as well as the autosomal recessive forms of sarcoglycanopathies. In these disorders, skeletal muscle disease usually appears in childhood with a typical DCM arising in the teenage years or early twenties. Both forms of myotonic muscular dystrophy, type 1 and type 2, can be associated with DCM. Atrial and ventricular arrhythmias are common in these tri- and tetra-nucleotide repeat expansion disorders. For several subtypes of genetic cardiomyopathy, arrhythmias may be the earliest manifestation. Myotonic dystrophy type 2 usually presents in older individuals, and the diagnosis can be easily missed especially if neuromuscular symptoms are not so pronounced.22
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
Gene editing has recently emerged as a very promising approach with the potential to eventually cure monogenic disorders such as HGPS. In 2019, two independent groups reported the use of CRISPR/Cas9-based technology to correct the HGPS-causing mutation in vivo in progeroid LmnaG609G/G609G mice [43,44]. Based on the normal phenotype and lifespan of mice that express lamin C but lack lamin A [36,39], the rationale behind both studies was to generate DNA double-strand breaks in Lmna exon 11 and/or 12 that, after repair by non-homologous end-joining, would generate insertions and deletions (indels) that abrogate progerin and lamin A expression without affecting lamin C levels. The molecular machinery needed for gene editing was packaged into modified adeno-associated virus 9 (AAV9) particles, which were systemically administered to newborn LmnaG609G/G609G mice as a single injection either intraperitoneally [43] or via the facial vein [44]. Indels in the Lmna gene were readily detected in liver (≈15–35% genomic copies) and less frequently in heart, muscle, and lung (≈1–5%). A reduction in the number of progerin-positive cells was detected in liver, heart, and muscle, but not in aorta, kidney, or lung [43]. Despite the limited extent of Lmna editing, CRISPR/Cas9-based treatment increased lifespan by ≈25% and ameliorated several progeroid features, including failure to thrive, hypoglycemia, bradycardia, impaired skeletal muscle function, heart perivascular fibrosis, and loss of aortic SMCs [43,44].
Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases
Published in Current Medical Research and Opinion, 2019
Camille Vatier, Marie-Christine Vantyghem, Caroline Storey, Isabelle Jéru, Sophie Christin-Maitre, Bruno Fève, Olivier Lascols, Jacques Beltrand, Jean-Claude Carel, Corinne Vigouroux, Elise Bismuth
Lipodystrophies are rare diseases, and the diagnosis is often overlooked33. LMNA-related lipodystrophy characteristics (e.g. generalized or partial fat atrophy with metabolic changes and insulin resistance) may be due to altered differentiation of adipocytes or changed fat structure34. The principal feature of FPLD2 is loss of fat, commencing at about pubertal age in women, in the buttocks, hips, limbs, and trunk, together with accumulation of fat in the axillae, back, face, labia majora, and visceral region. This distribution of fat, coupled with enhanced and well-defined musculature, means that affected women take on an android appearance. Further, phlebomegaly is often present in the upper and lower limbs, and the hands tend to be broad with small digits. Acanthosis nigricans in the axillae and neck and acrochordons, as signs of insulin resistance, are not infrequent. Women with FPLD2 frequently present with gynecologic disorders such as gestational diabetes, miscarriage, polycystic ovarian syndrome, and stillbirth35. In men, the abovementioned fat-loss changes occur later and are less evident; indeed, men with FPLD2 are typically diagnosed from female kin. Although subcutaneous lipomas are not present in all cases36, their presence should make physicians suspect FPLD2 when a background FPLD phenotype exists. The cardiovascular diversity of FPLD2 is broad and includes early atherosclerotic disease, arrhythmias, hypertrophic cardiomyopathy, and valvulopathies. Atherosclerotic disease and metabolic disturbances are less frequent in men than women with FPLD237.
Understanding left ventricular hypertrabeculation/noncompaction: pathomorphologic findings and prognostic impact of neuromuscular comorbidities
Published in Expert Review of Cardiovascular Therapy, 2019
Claudia Stöllberger, Josef Finsterer
When patients with LVHT are systematically referred to a myologist, a NMD might be found in up to 80% of the patients [17]. The NMDs most frequently associated with LVHT comprise mitochondrial disorders, Barth syndrome, zaspopathy, myotonic dystrophy type 1, dystrobrevinopathy, and Emery–Dreifuss muscular dystrophy owing to LMNA mutations (Table 6) [96]. Recently, a number of mutated new genes have been found that cause NMD, but without the presence of LVHT in any of the patients reported so far [35]. On the contrary, mutations in the same gene may be associated with LVHT but without the presence of NMD [35]. This phenotypic heterogeneity remains unexplained, but it is well-established that mutated genes may have a different phenotypic profile in different members of a family with LVHT [33].
Related Knowledge Centers
- Lamin
- Nuclear Lamina
- Prenylation
- Progeria
- Protein
- Phosphorylation
- Chromatin
- Gene
- Inner Nuclear Membrane Protein
- Mitosis