The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS, or progeria) is one of the rarest human diseases. Yet its study over the last decade has attracted attention from basic scientists, clinicians, the pharmaceutical industry, and policy makers. Why is the scientific community intensely watching the activity surrounding a disease that affects a mere 350 children worldwide ()? There are two important reasons. First, progress in HGPS can be viewed as a paradigm of modern translational medicine: basic science informing clinical medicine in a bench-to-bedside approach to medical discovery. Second, discoveries in rare diseases often offer new possibilities for understanding of cellular and organismal mechanisms, such as normal aging and cardiovascular disease in the case of HGPS. This Essay summarizes advances made in the understanding of HGPS and discusses the implications of research into rare diseases on basic cell biology, understanding of physiological processes, drug discovery, and clinical trial design.

Normally, lamin A is produced via a prelamin intermediate whose C-terminal cysteine residue is first modified by farnesylation and carboxymethylation followed by enzymatic cleavage of the terminal 15 amino acids, including the farnesylated cysteine, by the ZMPSTE24 endoprotease. However, in the HGPS mutant prelamin A isoform, this cleavage site is missing as a result of the aberrant splicing event. Thus, the HGPS mutation leads to the accumulation of a permanently farnesylated, uncleaved lamin A isoform named progerin ( Figure 1 ). This aberrantly modified, lamin A intermediate triggers, by yet-to-be discovered mechanisms, the many cellular and organismal disease symptoms.

The disease-causing mutation in HGPS activates what is normally a only sporadically used alternative splice site in LMNA exon 11, resulting in partial deletion of the exon ( Figure 1 ). Although the discovery of disease genes does not always inform about disease mechanism, the identification of an LMNA mutation as the cause of HGPS inspired intense basic and clinical research into this disease and its relationship to aging. The reason for the rapid progress in our understanding of HGPS was that the gene identification dovetailed with extensive prior work by basic cell biologists on the complex posttranslational processing events of lamin A, which would turn out to be key for understanding the HGPS disease mechanism ().

The mapping of the disease gene revealed that HGPS is a sporadic, autosomal dominant disease caused by a mutation in LMNA (). This gene codes for the inner nuclear membrane proteins lamins A and C, two prominent structural components of the eukaryotic cell nucleus. HGPS is a member of a group of diseases called laminopathies, resulting from mutations throughout the LMNA gene that result in a wide spectrum of overlapping disorders. These include muscular dystrophies, a peripheral neuropathy, lipodystrophy syndromes, and accelerated aging disorders ().

HGPS was first described by Drs. Jonathan Hutchinson and Hastings Gilford in 1886 and 1897, respectively (). For more than 100 years, its cause was a medical mystery. The disease was designated as a premature aging syndrome by Gilford based on the overall resemblance of patients to aged individuals and the presence of aging-associated symptoms, including lack of subcutaneous fat, hair loss, joint contractures, progressive cardiovascular disease resembling atherosclerosis, and death due to heart attacks and strokes in childhood () ( Figure 1 ).

HGPS is caused by a spontaneous point mutation in the LMNA gene, coding for the nuclear intermediate filament proteins lamin A and C. The disease mutation activates an alternative pre-mRNA splice site in exon 11 that results in removal of 150 nt from the 3′ end of this exon and creates an internal deletion of 50 aa in the translated lamin A protein. The mutant protein (red), referred to as progerin, is permanently farnesylated as the 50 aa deletion includes an endoproteolytic cleavage site, which normally removes the farnesylated C terminus from the wild-type protein. The farnesyl group is believed to facilitate the association of the protein to the nuclear membrane, resulting in its accumulation at the nuclear periphery. Association of progerin with the lamina interferes with normal lamina function and triggers, via yet unknown mechanisms, many of the commonly observed nuclear defects. HGPS cells also exhibit nonnuclear defects, including altered signaling and metabolic properties. It is assumed that these cellular defects and particularly the loss of stem cell function contribute to the prominent overt patient symptoms. (Left) Fluorescently tagged progerin (green) accumulates at the periphery of patient nuclei and alters nuclear morphology. (Right) Two progeria patients. Image reproduced with permission, courtesy of The Progeria Research Foundation.

Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages.

As in many diseases, tissue-specific cell lines from HGPS patients are not easily obtainable due to the difficulty of performing biopsies on frail patients. The development of patient-derived induced pluripotent stem (iPS) cells provides powerful tools to study differentiation pathways of tissues affected by the disease. HGPS iPS cells have been successfully generated and differentiated along multiple lineages, including the particularly disease-relevant vascular smooth muscle cells (VSMCs) and mesenchymal stem cells (). Early experiments using these cells revealed heightened sensitivity of HGPS mesenchymal stem cells to stress and aberrant differentiation of HGPS VMSCs (). Patient-derived iPS cells have also already been used to develop strategies that can successfully correct the HGPS mutation (), and, as with many other diseases, they will also be invaluable in screening approaches to identify possibly tissue-specific drugs. Finally, normal and gene-corrected HGPS iPS-derived tissue-specific cells may in the future provide a foundation for cell replacement therapy approaches to HGPS.

Functional studies using animal and cellular models of HGPS have facilitated the identification of regulatory and stress-response pathways involved in HGPS development. Of special interest is the hyperactivation of p53 signaling in HGPS cells and in mouse models of HGPS (). However, the fact that phenotype alterations in these progeroid mice are not completely rescued in a p53 null background indicates that other pathways contribute to the generation of the observed defects. These additional pathways may include the attrition of adult stem cells (), the dysregulation of the somatotrophic axis and several miRNA-controlled circuits (), the generation of profound changes in glucose and lipid metabolism (), and the ATM-dependent activation of NF-κB signaling that links nuclear lamina defects to the systemic inflammation observed in two different progeroid murine models ().

Suppression of proliferative defects associated with processing-defective lamin A mutants by hTERT or inactivation of p53.

Two other notable cellular defects in HGPS patient cells are widespread alterations of chromatin structure, such as the loss of heterochromatin domains, and changes in epigenetic markers. Using HGPS cells as a model system, the nucleosome-remodeling and deacetylase complex NURD has been identified as a mediator of both higher-order chromatin structure and maintenance of genomic integrity (). Using genome-wide studies in which the physical interactions of lamins with the genome are comparatively mapped in wild-type and patient cells, HGPS also provides an opportunity to probe lamin-genome interactions, which are increasingly recognized as key drivers of overall genome organization (). HGPS patient cells also suffer DNA repair defects due to both reduced recruitment of DNA damage response (DDR) factors to sites of damage and slowed repair kinetics (). On the other hand, the xeroderma pigmentosum group A (XPA) protein appears aberrantly recruited to replication forks, promoting replication fork stalling and activation of the DDR (). Progerin also appears to modulate telomere function and to induce DDR signaling from telomeres via activation of p53 and Rb pathways (). Interestingly, telomere dysfunction during senescence appears to feed back and promote progerin expression (). These studies have begun to uncover the elusive mechanisms that link nuclear structure and genomic instability.

The most overt cellular defects in HGPS are dramatic changes in nuclear morphology (), a phenotype that is not surprising given the prominent architectural role of lamin A in the nucleus. Whereas the lamin proteins in healthy cells move dynamically between the nuclear lamina polymer at the nuclear periphery and the nucleoplasm, they become immobilized in HGPS patient cells, leading to thickening of the lamina (). Probably as a consequence of these structural changes, the mechanical properties of HGPS nuclei are altered and patient cells exhibit increased stiffness compared with cells from healthy individuals (). These alterations are likely relevant in disease pathology, as they might affect the response of cells in tissues that are particularly exposed to mechanical stress such as the vasculature, bone, and joints—three tissues that exhibit some of the most prominent symptoms in HGPS patients. These defects are of great interest to the study of lamin biology because despite the known major functions of the nuclear lamins, the structural properties of the nuclear scaffold have remained elusive (). For example, it is unclear precisely how lamins polymerize and how they interact with a myriad of inner nuclear membrane complexes and chromatin or how they transmit mechanical signals to mechanosensitive genes. Lamin mutants such as the one causing HGPS are promising tools to begin to elucidate fundamental aspects of nuclear organization.

Elucidating the cascade of damaging events is a critical step in the understanding of any disease, and it is often crucial for identifying candidate drug targets. HGPS patient cells have numerous defects, and studying them has become a powerful tool for both basic scientists and clinicians to ask questions about the roles of major cellular processes in health and disease ( Figure 1 ).

What Progeria May or May Not Teach Us about Normal Aging

Rare diseases often reflect highly prevalent pathological events and provide a unique opportunity to study physiological processes. In the case of HGPS, the obvious question is whether the disease provides insights into normal aging and, because cardiovascular failure is the source of significant morbidity and mortality, into aging-related cardiovascular disease.

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MacRae V.E. The role of cellular senescence during vascular calcification: a key paradigm in aging research. The cardiovascular system is of crucial importance in HGPS, as cardiovascular failure is the source of significant morbidity and almost all mortality. From a clinical perspective, HGPS is a primary vasculopathy, characterized by early and pervasive accelerated vascular stiffening followed by hypertension, vessel plaques, angina, cardiomegaly, metabolic syndrome, and congestive heart failure (). Isolated from risk factors such as hypercholesterolemia and increased C-reactive protein (), early stage hypertension, and smoking, the study of HGPS could provide an opportunity to discover new elements that may influence the vascular disease component of aging. For example, the abnormally dense vascular adventitia observed in individuals with HGPS may contribute to their vessel stiffening, and the role of the adventitia in the pathobiology of generalized CVD during aging is just beginning to be explored (). Additionally, HGPS has shed light on mechanisms of vascular calcification in aging and atherosclerosis. Excess prelamin A or progerin results in calcium dysfunction (), and prelamin A promotes VSMC calcification and aging by inducing persistent DNA damage signaling (). HGPS patients suffer from extraskeletal calcium phosphate deposition, which potentially acts as an important factor for vascular plaque development (). These studies that show connections between cellular senescence, generalized calcium dysfunction, vascular calcification, and atherosclerotic plaque formation in both aging and HGPS represent emerging areas of cross-discovery in both basic and clinical research arenas ().

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et al. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion. Notably, some key aspects of aging are not recapitulated in HGPS. Most prominent among these are the absence of nervous system deterioration, including dementia, and the lack of detectable immune system deficits. Recent studies have shown that progerin levels in the brain are very low and that the microRNA miR-9 downregulates lamin A synthesis in the brain (). These results suggest that the lack of symptoms in the CNS of HGPS patients may be due to an absence of progerin in neural cells. This may also be the case for the absence of immune system deficiencies. Moreover, the paucity of reports on tumors or cancers in HGPS patients implies low susceptibility of their cells to malignant transformation, in contrast to the strong increase in tumor susceptibility during normal aging. The lack of tumors in HGPS patients is even more surprising, given the persistently high levels of DNA damage in HGPS cell lines. Interestingly, recent studies using ZMPSTE24 mosaic mice have revealed that prelamin A accumulation prevents cancer invasion and results in a decrease in the incidence of infiltrating carcinomas in association with altered extracellular matrix components ().

Like any premature aging syndrome, HGPS is only a partial representation of the multifactorial process of normal aging. However, rather than using discrepancies as an argument to diminish the potential of HGPS to provide insight into normal aging, a more productive approach may be to carefully elucidate the intersections and distinctions between HGPS and normal aging in order to gain new understanding within both fields.