Cardiovascular findings of Hutchinson-Gilford syndrome: a Doppler and two-dimensional echocardiographic study

Ha, Jong Won; Shim, Won Heum; Chung, Nam Sik

doi:10.3349/ymj.1993.34.4.352

Cited by 12 publications

(6 citation statements)

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“…HGPS minipigs develop both systolic and diastolic dysfunction (including left atrial enlargement suggesting elevated LV filling pressure), which are common underlying causes of heart failure. Also consistent with reports in HGPS patients 6,7,32,37–40 , we found signs of mild mitral valve degeneration accompanied by mild mitral regurgitation in two of eight HGPS minipigs.…”

Section: Discussionsupporting

confidence: 92%

Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome

et al. 2019

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Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous LMNA c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients.

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Section: Discussionsupporting

confidence: 92%

Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome

et al. 2019

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“…(5E)). Cardiovascular findings reported in HGPS and progeroid syndromes include concentric leftventricular myocardial hypertrophy with raised left-ventricular pressures, fibrotic nodules inserted on thickened aortic cusps, calcification of the posterior annulus and moderate aortic and mitral regurgitations [191,194]. Classical HGPS results from the heterozygous c.1824 C>T (p.G608G) mutation that activates a cryptic splice site and results in a 50 amino acid deletion, affecting lamin A only [192,193].…”

Section: V3 Hutchinson-gilford Progeriamentioning

confidence: 97%

The Nuclear Envelope, a Key Structure in Cellular Integrity and Gene Expression

Verstraeten

Broers²,

Ramaekers³

et al. 2007

CMC

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The envelope that encapsulates the cell nucleus has recently gained considerable interest, as several clinical syndromes are linked to mutations in its molecular components. Most disorders recognized so far are caused by defects in the nuclear lamins, building blocks of a filamentous network lining the nucleoplasmic side of the inner nuclear membrane. Nuclear lamins are the evolutionary precursors of cytoskeletal intermediate filaments and associate in a head-to-tail manner into a stable lamina at the nuclear periphery and into a more dispersed structure in the nucleoplasm. Lamins have a scaffolding function for several nuclear processes such as transcription, chromatin organization and DNA replication, and maintain nuclear and cellular integrity. Mutations in the LMNA gene, encoding A-type lamins, can cause cardiac and skeletal muscle disease, lipodystrophy and premature ageing phenotypes. Hence, the integrity of the nuclear envelope seems essential for longevity. Furthermore, the laminopathies provide evidence that metabolism and ageing are as tightly linked in humans as they are in model organisms such as C. elegans. In this review, we elaborate on the structure and functions of nuclear lamins, the spectrum of syndromes related to mutations in nuclear envelope components and pathogenic concepts unifying these disorders.

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“…Nevertheless, HGPS vessels also uniquely feature prominent adventitial thickening and fibrosis (14,79). Another feature of physiological aging also found in HGPS is vascular calcification (VC), which is associated with augmented CVD-associated morbimortality in the general population (80); VC affects the aorta and aortic and mitral valves of some HGPS patients, and can cause aortic and/or mitral regurgitation (14,75,(81)(82)(83)(84). Neuroimaging studies in a 25-patient cohort identified early and clinically silent stroke as a prevalent characteristic of HGPS (85).…”

Section: Cvd In Hgps Patientsmentioning

confidence: 99%

Aging in the Cardiovascular System: Lessons from Hutchinson-Gilford Progeria Syndrome

Hamczyk

Campo

Andrés

2018

Annu. Rev. Physiol.

103

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Aging, the main risk factor for cardiovascular disease (CVD), is becoming progressively more prevalent in our societies. A better understanding of how aging promotes CVD is therefore urgently needed to develop new strategies to reduce disease burden. Atherosclerosis and heart failure contribute significantly to age-associated CVD-related morbimortality. CVD and aging are both accelerated in patients suffering from Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder caused by the prelamin A mutant progerin. Progerin causes extensive atherosclerosis and cardiac electrophysiological alterations that invariably lead to premature aging and death. This review summarizes the main structural and functional alterations to the cardiovascular system during physiological and premature aging and discusses the mechanisms underlying exaggerated CVD and aging induced by prelamin A and progerin. Because both proteins are expressed in normally aging non-HGPS individuals, and most hallmarks of normal aging occur in progeria, research on HGPS can identify mechanisms underlying physiological aging.

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Cardiovascular findings of Hutchinson-Gilford syndrome: a Doppler and two-dimensional echocardiographic study

Cited by 12 publications

References 0 publications

Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome

Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome

The Nuclear Envelope, a Key Structure in Cellular Integrity and Gene Expression

Aging in the Cardiovascular System: Lessons from Hutchinson-Gilford Progeria Syndrome

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