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Progeria or Hutchinson-Gilford progeria Syndrome

Progeria or Hutchinson-Gilford progeria Syndrome

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Angina, shortness of breath, and sweating are just a few symptoms that may indicate a heart attack. Treatment of heart disease involves control of heart disease risk factors through lifestyle changes, medications, and/or stenting or bypass surgery. Heart disease can be prevented by controlling heart disease risk factors.

Progeroid syndrome with Ehlers-Danlos features is an extremely rare genetic disorder characterized in newborns by a “progeria-like” (progeroid) appearance. The skin may be wrinkled leading to an aged appearance. Other symptoms include sparse eyebrows, scanty eyelashes, multiple birthmarks, and extremely fragile skin which bruises easily. Some children with this disorder may have low-set prominent ears, a receding chin, and/or irregular teeth.

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Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease most commonly caused by a heterozygous mutation (c.1824C > T and p.G608G) in exon 11 of LMNA, the gene encoding the A-type lamins A and C (De Sandre-Giovannoli et al. 2003; Eriksson et al. 2003). Nuclear lamins are type V intermediate filament proteins and the main components of a filamentous meshwork underlying the inner nuclear membrane (INM), called the nuclear lamina (Dechat et al. 2010a; Gruenbaum and Foisner 2015; Osmanagic-Myers et al. 2015). Lamins provide shape and structural stability to the nucleus but are also involved in many essential cellular processes, such as DNA replication and repair, gene expression, chromatin organization, mechanosensing, and cell proliferation and differentiation. Based on sequence similarities, developmentally regulated gene expression patterns, and biochemical properties, they are classified into A- and B-type lamins. While the major B-type lamins, lamins B1 and B2, are encoded by distinct genes (LMNB1 and LMNB2, respectively), all A-type lamins, of which lamins A and C are the major isoforms, are derived from LMNA by alternative splicing. B-type lamins and lamin A are initially expressed as prelamins and undergo multiple steps of post-translational modifications at their C-terminal –CaaX sequence, including farnesylation and carboxymethylation of the cysteine residue (Rusinol and Sinensky 2006). While B-type lamins remain farnesylated and carboxymethylated, prelamin A is further processed by the zinc metalloprotease related to Ste24p (Zmpste24/FACE1), which removes the 15 C-terminal amino acids, including the farnesylated and carboxymethylated cysteine residue (Pendas et al. 2002). As a consequence, mature lamin A and lamin C, which never becomes farnesylated since it lacks a –CaaX box, are less lipophilic than B-type lamins and therefore are not only present at the nuclear lamina but also distributed throughout the nucleoplasm as a highly dynamic pool (Moir et al. 2000; Dechat et al. 2010b; Kolb et al. 2011).

Kane et al. reported a family in which 5 individuals had a progeroid syndrome with prominent cutaneous and cardiovascular manifestations. The proband and her sister were described in detail. Both were normal at birth, but lost eyebrows and eyelashes in childhood. In their late twenties, both showed a progeroid appearance and developed exertional dyspnea associated with mitral valve calcification and stenosis necessitating valve replacement; the proband also had aortic stenosis. The proband developed occlusion of the coronary arteries and died of acute myocardial infarction at age 44; her sister died of intracranial hemorrhage at age 34. Both women also had several primary malignancies, including basal and squamous cell carcinomas, papillary renal carcinoma, and carcinoid tumor. Family history revealed a father, paternal uncle, and paternal grandfather with premature aging and significant cardiac disease resulting in death between ages 29 and 44 years. Kane et al. proposed the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder.

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Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs). As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent 'drug of hope' for Hutchinson-Gilford progeria syndrome (HGPS) and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.

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