genetics of aging, progeria and lamin disorders

Genetics of aging, progeria and lamin disordersShrestha Ghosh1 and Zhongjun Zhou1,2

Available online at www.sciencedirect.com

ScienceDirect

Premature aging disorders, like Werner syndrome, Bloom’s

syndrome, and Hutchinson–Gilford Progeria Syndrome

(HGPS), have been the subjects of immense interest as they

recapitulate many of the phenotypes observed in physiological

aging. They, therefore, not only provide model systems to study

normal aging processes but also give valuable insights into the

intricate mechanisms underlying senescence. Recent works on

HGPS have revealed alterations in a spectrum of cellular and

molecular pathways involved in the maintenance of genomic

integrity, thus suggesting a profound impact of the nuclear

lamina in nuclear organization, chromatin dynamics, regulation

of gene expression and epigenetics.

Addresses1 Department of Biochemistry, Li Ka Shing Faculty of Medicine, The

University of Hong Kong, Hong Kong2 Shenzhen Institute of Research and Innovation, The University of Hong

Kong, Shenzhen, China

Corresponding author: Zhou, Zhongjun ([email protected])

Current Opinion in Genetics & Development 2014, 26:41–46

This review comes from a themed issue on Molecular and genetic

bases of disease

Edited by Cynthia T McMurray and Jan Vijg

http://dx.doi.org/10.1016/j.gde.2014.05.003

0959-437X/# 2014 Elsevier Ltd. All rights reserved.

IntroductionAging broadly refers to the gradual deterioration of

physical and psychological abilities accompanied by a

decline in the proper body functioning and resistance

to the threats that an individual is exposed to. In the past

few decades, this field has ignited interest in scientific

communities especially because its underlying mechan-

isms began to be unveiled. Although several cellular

pathways have emerged as key players in the process

of biological aging, a significant proportion of them even-

tually converge as the threats being posed on genomic

integrity [1,2]. The insults to genomic stability have

further evolved as causative factor of several premature

aging syndromes like Cockayne syndrome, Werner syn-

drome, HGPS and many more [3]. Here, we review the

genetic alterations leading to progeroid syndromes

(especially progeria) and other laminopathies.

www.sciencedirect.com

Physiological and premature aging: from theperspective of geneticsThe prominence of genetic contribution to aging was

primarily advocated by two theories, somatic mutation

theory of aging and DNA damage theory of aging [4,5].

Further, the infliction of insults on genomic DNA from

intercalating agents, radiation, reactive oxygen species

(ROS), and DNA double strand breaks have been

reported to contribute to premature aging phenotypes

in several mice models [6–8]. Additionally, in human

progeroid syndrome HGPS, delayed recruitment of

DNA-damage checkpoint response proteins has been

established as a causative factor for accrued genomic

instability [9]. Similarly, mutation/deletion of several

genes has been shown to accelerate or delay aging pro-

cess. For example, Sirt6-deficient mice display premature

aging phenotypes accompanied with genomic instability

[10]. Mutation in the Insulin/Insulin like growth factor

(IGF1) receptor gene daf-2 has been reported to double

the lifespan of C. elegans [11]. Also, mitochondrial DNA

(mtDNA) mutations result in aging phenotypes in the

mtDNA mutator mouse models [12]. Taken together,

these studies clearly suggest a pivotal part played by

genome maintenance and DNA damage repair in the

process of cellular senescence and aging.

Progeroid syndromes: a genetic backgroundProgeroid or premature aging syndromes are a class of

rarely occurring genetic disorders. They can be broadly

classified into unimodal progeroid syndromes (affecting

only one tissue type) and segmental progeroid syndromes

(affecting several tissues and displaying some but not all

symptoms of normal physiological aging). Familial Alz-

heimer’s disease and Parkinson’s disease fall under the

first category. The segmental progeroid syndromes large-

ly comprise of monogenic disorders with malfunction

arising from single gene mutations in the affected indi-

viduals. Some of the most widely studied examples are

Cockayne syndrome, Werner syndrome, HGPS and

Bloom’s syndrome. They can be further categorized into

four groups based on the type of genes being mutated

(Figure 1) [13–15]. However, the extrapolation of pre-

mature aging to physiological aging has often been

debated since these syndromes recapitulate only a frac-

tion of the alterations observed in normal aging process

and hence might present highly specialized physiological

conditions [16,17]. However, recent studies in HGPS

have gained limelight in connecting premature aging to

normal aging. The findings such as existence of progerin

expression in normal individuals and increase in the level

of progerin in the tissues of coronary arteries with gradual

aging, further support this idea [18].


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42 Molecular and genetic bases of disease

Figure 1

Segmental Progeroid SyndromeUnimodal Progeroid Syndrome

Nucleotide excisionrepair (NER) genes

Other DNA damagesignaling genes

RECQL mutatedgenes

LMNA/ZMPSTE24mutated genes

XerodermaPigmentosum

Bloom’ssyndrome

Hutshinson-Gilford

Progeriasyndrome

AtaxiaTelangiectasia

mutated

RestrictiveDermopathy

Wernersyndrome

RothmundThomsonsyndrome

CockayneSyndrome

Trichothio-dystrophy

Alzheimer’sdisease

Parkinson’sdisease

Progeroid Syndromes (PS)

Current Opinion in Genetics & Development

Categorization of progeroid syndromes: progeroid syndromes can be broadly classified on the basis of number and type of affected tissues and also

on the type of genes mutated/deleted.

Progeria: underlying genetic mechanismsHutchinson–Gilford progeria syndrome (HGPS) is a rare

and severe early onset progeroid syndrome. It was first

reported more than a century ago by Jonathan Hutchinson

in 1886 and Hastings Gilford in 1897 independently

(hence the name HGPS). It gained limelight in 2003

when its underlying genetic defect was discovered. Pro-

geria is characterized predominantly by a unique hetero-

zygous autosomal de novo point mutation in LMNA gene

(C1824 T) which codes for the nuclear lamina protein

lamin A [19,20]. The major nuclear lamin proteins

expressed in humans are lamins A, C, B1, B2 and B3

encoded by the genes LMNA (for both lamins A and C),

LMNB1 and LMNB2 (for both lamins B2 and B3), respect-

ively [21]. These proteins form the only class of inter-

mediate filament proteins in the nucleus which support

the structure and shape of the nucleus, anchor chromatin

and also tether nuclear pore complexes in their appro-

priate functional positions [22]. Lamin A (LA) is pro-

cessed from its precursor prelamin A which contains a

CaaX motif at its C terminal. This Cysteine residue

undergoes farnesylation which leads to the cleavage of

the aaX group followed by a methyl esterification of the

Cysteine residue by isoprenylcysteine carboxyl methyl-

transferase (ICMT). This activates cleavage of an

additional 15 amino acids of the precursor by the metallo-

proteinase, ZMPSTE24, to generate mature lamin A [23].


In HGPS, a single base substitution (C1824T) in the

LMNA gene activates a cryptic splice site within exon

11, giving rise to a 50 amino acids deleted prelamin A

termed as Progerin that lacks the second cleavage (of 15

amino acids). This farnesylated progerin is considered

toxic to the cells [19,20]. Many mouse models have been

developed so far to study progeria, including Zmpste24�/�

mice, G608G BAC transgenic mice, Keratin 14-progerin

transgenic mice, and Lmna G609G knock-in mice [24].

The pathology of progeria is attributable to several

genetic defects (Figure 2) [25]. Some of them are

described below.

Telomere dysfunctionAging has time and again been associated with accumu-

lation of DNA lesions and defects in DNA damage repair

mechanisms. Telomere shortening and dysfunction is a

chief contributor to this DNA damage and poses serious

threat to the integrity of genome [25]. Telomere attrition

is also a major hallmark of aging and cellular senescence

[26–29]. Mammalian telomeres essentially comprise of

hexameric sequence repeats TTAGGG and the shelterin

protein complex capping the telomere ends [30]. The

telomeres shorten after each replication cycle as DNA

polymerase cannot extend till its extreme end, thereby

generating DNA-damage checkpoint response signaling.

This eventually gets accrued on to elicit an irreversible


Chromatin remodeling defects in progeria Ghosh and Zhou 43

Figure 2

Epigeneticalterations

Telomeredysfunction

Altered gene-proteininteractions

LMNA genemutations

Hutchinson-Gilford

progeriasyndrome

(HGPS)Chromatin

remodeling defects

Symptoms observed:

Alopecia

Atherosclerosis

Cachexia

Kidney failure

Scleroderma

Cardiovascular problems

Cellular phenotypes:

Hterochromatin loss

Nuclear lobulation

Increased apoptosis

Impaired DNA damage repair

Mitochondrial dysfunction

Cell-cycle regulation defects

Current Opinion in Genetics & Development

Defective genetic pathways and consequences of HGPS: several defects in different genetic pathways contribute to the cellular malfunctions and

severe symptoms observed in Hutchinson–Gilford Progeria Syndrome patients.

growth arrest, eventually resulting in senescence [31–33].

Recent studies suggest an inter-play between progerin

accumulation and telomere dysfunction. In HGPS cells, it

is reported that telomerase, a telomere-elongating ribo-

nucleoprotein comprising a reverse transcriptase (TERT)

and RNA component (TERC), extends cellular lifespan

by toning down the DNA damage signaling triggered by

progerin. In addition, progerin-induced DNA damage

signaling is shown to concentrate in telomeres and majorly

associate with telomere aggregates [34�,35]. On the other

hand, fibroblast clones from HGPS patients have shown to

senesce even after reinstating telomere length and activity

[36]. Taken together, the cause and effect of telomere-

progerin relationship still remains largely elusive. Intrigu-

ingly, a recent publication demonstrated that lamin A

Dexon9 mutation caused telomere and chromatin defects

but did not result in genomic instability [37]. Thus the

mechanistic link between telomere attrition, progerin

accumulation and genomic instability and their inter-

dependence on each other still needs further investigation

to draw a more concrete conclusion.

Perturbed epigenetic regulationEpigenetic modifications like DNA methylation, acety-

lation, phosphorylation, and ubiquitylation, are known to


regulate the dynamics of chromatin organization. DNA

methylation typically characterizes heterochromatin

(the more transcriptionally silent form) while acetylated

N-terminal histone tails promote euchromatin formation

(the actively transcribing form) [38,39]. As observed in

cellular senescence, HGPS fibroblasts also show marked

decline in heterochromatin markers like histone H3

lysine 9 methylation (H3K9me) and HP1 proteins that

further decrease with passage [40–42]. Interestingly, our

recent data demonstrated an increase in H3K9 trimethy-

lation in Zmpste24�/� cells due to elevation in SUV39H1

(methyltransferase responsible for H3K9me3) levels

[43�]. This discrepancy was attributable to the difference

in passage numbers of the primary human cells used in

experimentation as perfectly matched wildtype primary

dermal fibroblasts are unlikely to be obtained. To this

end, data from mice are more reliable. Our data estab-

lished that SUV39H1 depletion could partially alleviate

DNA damage repair and delay senescence in progeroid

cells. Other epigenetic modifications like downregulated

H3K27 trimethylation and upregulated H4K20 trimethy-

lation have also been reported in HGPS cells [44,45]. Our

previous report also identified H4K16 hypoacetylation

in Zmpste24�/� mice [46]. In addition, we showed that

decrease in H4K16 acetylation could also be observed in



normally aging cells. This epigenetic modification led to

improper recruitment of damage repair proteins to DNA

lesions. Treatment of the mutant mice with HDAC

inhibitor, Sodium Butyrate (NaB), restored the acety-

lation level of H4 and partially rescued the progeroid

features in mice. This finding provides a novel thera-

peutic strategy for progeria. On the whole, these reports

suggest that targeting epigenetic modifiers can have

potential benefits in the intervention of premature aging.

Chromatin remodeling: an emerging player inpremature agingA plethora of ATP-dependent or covalently modifying

remodeling factors largely regulates chromatin structure

and compaction that determines DNA accessibility to

several chromatin-associated factors required for DNA

replication, transcription and damage repair. The identi-

fication of NURD (Nucleosome Remodeling Deacety-

lase) complex’s pivotal role in aging further strengthened

this idea [47]. NURD is a chromatin remodeling complex

containing seven subunits which primarily function in

histone deacetylation and methyl-CpG binding [48].

HGPS cells as well as normally aged cells show decline

in several NURD components like HDAC1 and histone

chaperones RBBP4. It is also reported that knockdown of

NURD components reiterates chromatin defects and

DNA damage observed in aging [47]. Similarly, histone

H4K20 methylase SET8 has also been demonstrated to

elevate DNA damage when depleted in normal cells [49].

In addition to these, our recent study identified defective

ATM-Kap1 signaling as a major contributor to DNA

damage repair defects observed in Zmpste24�/� MEFs

(mouse embryonic fibroblasts). We also showed that Kap-

1 knockdown could rescue those defects along with

chromatin remodeling impairments and delay senescence

in the mutant MEFs [50]. Recently, it has also been

reported that decreased ICMT activity resulted in pre-

lamin A mislocalization, causing enhanced AKT- mam-

malian target of rapamycin (mTOR) signaling and

delayed senescence in HGPS fibroblasts [51��]. Apart

from these, our research on mammalian sirtuin SIRT1

(class III histone deacetylase and mono-ADP ribosyl-

transferase) has yielded very promising results and pro-

vided a novel mechanistic explanation to resveratrol’s

anti-aging effects [52�]. Taken together, the above find-

ings clearly advocate a promising role for the chromatin

modifiers in understanding the intricate molecular mech-

anisms underlying premature senescence.

Altered protein interactionsIt is reported that progerin elicits chromatin organization

changes globally by increasing interactions with a specific

subset of genes in addition to those that are associated

with lamin A [53]. In addition, the inner nuclear mem-

brane protein SUN1 is observed to over-accumulate in

HGPS cells and LMNA mutant fibroblasts. Minimizing

this over-accumulation ameliorated nuclear defects and


cellular senescence [54�]. Several such protein interaction

defects have been reported which also partly explain the

pathology of progeria. For example, altered interaction in

between lamin A/progerin and various transcription fac-

tors like PRX1, MEOX/GAX, TWIST2, have been

described to contribute to progeroid phenotypes [25].

Atypical HGPS conditionsApart from the known heterozygous point mutation

C1824 T observed in classical HGPS, two recent reports

described that a C1579 T missense mutation in exon 9

results in R527 C substitution causing progeria [55,56�].This homozygous mutation caused several typical HGPS

phenotypes in the patients along with digestive system

disorders and more severe skeletal damage. In both cases,

the siblings were homozygous while their parents were

heterozygous for this mutation. In addition, three differ-

ent substitutions at the 527 coding site in LMNA gene viz.

R527P, R527H and R527C/R471C cause different dis-

orders like Emery–Dreifuss Muscular dystrophy and

mandibuloacral dysplasia [56]. Intriguingly, homozygous

mutation G1626G, that is p.K542N affecting both lamins

A and C is also observed to cause HGPS [57]. This study

challenged the concept of only lamin A mutations to be

responsible for causing HGPS. Another report revealed

an additional heterozygous mutation in LMNA gene

G1821A causing neonatal progeria [58]. These reports

are thus suggestive of the existence of varied forms of

point mutations in LMNA gene that can also result in

progeroid phenotypes.

Other lamin disordersTill date, nearly 15 disorders have been attributed to

LMNA mutations. These disorders arising from defects in

nuclear lamin genes are collectively termed as lamino-

pathies. Apart from the accelerated aging syndromes like

HGPS, atypical Werner syndrome, and Restrictive der-

mopathy (also caused by loss of ZMPSTE24 gene), lamin

related disorders also encompass several striated muscle

diseases, peripheral nerve disorders, lipodystrophy, and

bone diseases [59]. LMNA gene mutations like Emery–Dreifuss muscular dystrophy and Limb-girdle muscular

dystrophy also result in dilated cardiomyopathy which

causes mortality. Apart from these, deletion mutation in

ZMPSTE24 gene results in partially mature lamin A and

causes Mandibuloacral dysplasia and Restrictive dermo-

pathy. Furthermore, homozygous loss of lamin A function

results in peripheral nerve myelination loss, thereby

causing Charcot–Marie tooth syndrome. Mutations in

LMNB1 and LMNB2 also result in adult-onset lipodystro-

phy and partial lipodystrophy respectively. In addition,

homozygous and heterozygous mutations in the lamin B

receptor (LBR) cause Greenberg skeletal dysplasia and

Pelger–Huet anomaly respectively [60]. This whole spec-

trum of laminopathies clearly indicates the significance of

nuclear lamin genes in maintaining genomic integrity and

proper cellular functioning.


Chromatin remodeling defects in progeria Ghosh and Zhou 45

DiscussionSo far, there have been numerous studies highlighting the

importance of genetics in the field of premature aging

related disorders. With upcoming reports on several gene

functions, the genetic mechanisms underlying these dis-

orders are becoming clearer. Several novel studies are

being carried out in order that not only lifespan but also

healthspan of individuals could be enhanced. However,

the complications associated with progeria are numerous

making it more challenging to devise one solution for

targeting all of them. But, with the advent of several

promising genetic approaches, it is expected that an

effective therapy could be devised to ameliorate the

severe progeroid phenotypes observed in patients.

AcknowledgementsWe would like to acknowledge the supports from National Natural ScienceFoundation of China (81330009), Chinese Ministry of Science andTechnology (973 Project 2011CB964700), and Hong Kong ResearchCouncil CRF (HKU2/CRF/13G).

References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:

� of special interest

�� of outstanding interest

1. Kirkwood TB: A systematic look at an old problem. Nature 2008,451:644-647.

2. Gems D, Partridge L: Genetics of longevity in model organisms:debates and paradigm shifts. Annu Rev Physiol 2013, 75:621-644.

3. Wolters S, Schumacher B: Genome maintenance andtranscription integrity in aging and disease. Front Genet 2013,4:19.

4. Vijg J: Somatic mutations and aging: a re-evaluation. Mutat ResFund Mol Mech Mutagen 2000, 447:117-135.

5. Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A,Budovsky A, Yanai H, Fraifeld VE: The role of DNA damage andrepair in aging through the prism of Koch-like criteria. AgeingRes Rev 2012, 12:661-684.

6. Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J: Aging andgenome maintenance: lessons from the mouse? Science 2003,299:1355-1359.

7. Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M,Alt FW: DNA repair, genome stability, and aging. Cell 2005,120:497-512.

8. De Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, vanSteeg H, Weeda G, Horst GTJ, Leeuwen WV, Themmen APN et al.:Premature aging in mice deficient in DNA repair andtranscription. Science 2002, 296:1276-1279.

9. Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD,Li KM, Chau PY, Chen DJ et al.: Genomic instability inlaminopathy-based premature aging. Nat Med 2005, 11:780-785.

10. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR,Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM et al.:Genomic instability and aging-like phenotype in the absenceof mammalian SIRT6. Cell 2006, 124:315-329.

11. Kenyon CJ: The genetics of ageing. Nature 2010, 464:504-512.

12. Edgar D, Larsson NG, Trifunovic A: Point mutations are causingprogeroid phenotypes in the mtDNA mutator mouse. CellMetabol 2010, 11:1.


13. Navarro CL, Cau P, Levy N: Molecular bases of progeroidsyndromes. Hum Mol Genet 2006, 15:151-161.

14. Yin D, Chen K: The essential mechanisms of aging: irreparabledamage accumulation of biochemical side-reactions. ExpGerontol 2005, 40:455-465.

15. Hirschfeld G, Berneburg M, von Armin C: Progeroid-syndrome.Dtsch Arztebl 2007, 104:346-353.

16. Kipling D, Davis T, Ostler EL, Faragher RG: What can progeroidsyndromes tell us about human aging? Science 2004,305:1426-1431.

17. Dreesen O, Stewart CL: Accelerated aging syndromes, are theyrelevant to normal human aging? Aging 2011, 3:889.

18. Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, Erdos MR,Blair C, Funke B, Smoot L: Cardiovascular pathology inHutchinson–Gilford progeria: correlation with the vascularpathology of aging. Arterioscler Thromb Vasc Biol 2010, 30:2301-2309.

19. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J,Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M et al.:Lamin a truncation in Hutchinson–Gilford progeria. Science2003, 300:2055.

20. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L,Erdos MR, Robbins CM, Moses TY, Berglund P et al.: Recurrentde novo point mutations in lamin A cause Hutchinson–Gilfordprogeria syndrome. Nature 2003, 423:293-298.

21. Gerace L, Blum A, Blobel G: Immunocytochemical localizationof the major polypeptides of the nuclear pore complex-laminafraction. Interphase and mitotic distribution. J Cell Biol 1978,79:546-566.

22. Gerace L, Huber MD: Nuclear lamina at the crossroads of thecytoplasm and nucleus. J Struct Biol 2012, 177:24-31.

23. Weber K, Plessmann U, Traub P: Maturation of nuclear lamin Ainvolves a specific carboxy-terminal trimming, which removesthe polyisoprenylation site from the precursor; implicationsfor the structure of the nuclear lamina. FEBS Lett 1989,257:411-414.

24. Zhang H, Kieckhaefer JE, Cao K: Mouse models oflaminopathies. Aging Cell 2013, 12:2-10.

25. Prokocimer M, Barkan R, Gruenbaum Y: Hutchinson–Gilfordprogeria syndrome through the lens of transcription. Aging Cell2013, 12:533-543.

26. Decker ML, Chavez E, Vulto I, Lansdorp PM: Telomere length inHutchinson–Gilford progeria syndrome. Mech Ageing Dev2009, 130:377-383.

27. Sahin E, DePinho RA: Linking functional decline of telomeres,mitochondria and stem cells during ageing. Nature 2010,464:520-528.

28. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV,Futcher AB, Greider CW, Harle CB: Telomere length predictsreplicative capacity of human fibroblasts. Proc Natl Acad Sci US A 1992, 89:10114-10118.

29. Chang E, Harley CB: Telomere length a replicative aging inhuman vascular tissues. Proc Natl Acad Sci U S A 1995,92:11190-11194.

30. de Lange T: How telomeres solve the end-protection problem.Science 2009, 326:948-952.

31. Calado RT, Young NS: Telomere diseases. N Engl J Med 2009,361:2353-2365.

32. Armanios M: Syndromes of telomere shortening. Annu RevGenomics Hum Genet 2009, 10:45-61.

33. Mitteldorf JJ: Telomere biology: cancer firewall or aging clock?Biochemistry 2013, 78:1054-1060.

34.�

Cao K, Blair CD, Faddah DA, Kieckhaefer JE, Olive M, Erdos MR,Nabel EG, Collins FS: Progerin and telomere dysfunctioncollaborate to trigger cellular senescence in normal humanfibroblasts. J Clin Investig 2011, 121:2833-2844.


http://refhub.elsevier.com/S0959-437X(14)00050-1/sbref0005







































































































This paper demonstrated that telomere attrition lead to increased pro-gerin production in human fibroblasts, thus inferring that telomere dys-function could be a leading cause of cellular senescence.

35. Benson EK, Lee SW, Aaronson SA: Role of progerin-inducedtelomere dysfunction in HGPS premature cellular senescence.J Cell Sci 2010, 123:2605-2612.

36. Wallis CV, Sheerin AN, Green MH, Jones CJ, Kipling D,Faragher RG: Fibroblast clones from patients with Hutchinson–Gilford progeria can senesce despite the presence oftelomerase. Exp Gerontol 2004, 39:461-467.

37. Das A, Grotsky DA, Neumann MA, Kreienkamp R, Gonzalez-Suarez I, Redwood AB, Kennedy BK, Stewart CL, Gonzalo S:Lamin A Dexon9 mutation leads to telomere and chromatindefects but not genomic instability. Nucleus 2013, 4.

38. Bird A: Perceptions of epigenetics. Nature 2007, 447:396-398.

39. Kouzarides T: Chromatin modifications and their function. Cell2007, 128:693-705.

40. Scaffidi P, Misteli T: Reversal of the cellular phenotype in thepremature aging disease Hutchinson–Gilford progeriasyndrome. Nat Med 2005, 11:440-445.

41. Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR,Erdos MR, Eriksson R, Goldman AE, Khuon S, Collins FS: Mutantnuclear lamin A leads to progressive alterations of epigeneticcontrol in premature aging. Proc Natl Acad Sci U S A 2006,103:8703-8708.

42. Scaffidi P, Misteli T: Lamin A-dependent nuclear defects inhuman aging. Science 2006, 312:1059-1063.

43.�

Liu B, Wang Z, Zhang L, Ghosh S, Zheng H, Zhou Z: Depleting themethyltransferase Suv39h1 improves DNA repair and extendslifespan in a progeria mouse model. Nat Commun 2013, 4:1868.

This study highlighted the efficacy of chromatin remodelers in ameliorat-ing progeroid phenotypes.

44. Columbaro M, Capanni C, Mattioli E, Novelli G, Parnaik VK,Squarzoni S, Maraldi NM, Lattanzi G: Rescue of heterochromatinorganization in Hutchinson–Gilford progeria by drugtreatment. Cell Mol Life Sci 2005, 62:2669-2678.

45. Sedivy JM, Banumathy G, Adams PD: Aging by epigenetics — aconsequence of chromatin damage? Exp Cell Res 2008,314:1909-1917.

46. Krishnan V, Chow MZY, Wang Z, Zhang L, Liu B, Liu X, Zhou Z:Histone H4 lysine 16 hypoacetylation is associated withdefective DNA repair and premature senescence in Zmpste24-deficient mice. Proc Natl Acad Sci U S A 2011, 108:12325-12330.

47. Pegoraro G, Kubben N, Wickert U, Gohler H, Hoffman K, Misteli T:Aging-related chromatin defects via loss of the NURDcomplex. Nat Cell Biol 2009, 11:1261-1267.

48. Allen HF, Wade PA, Kutateladze TG: The NuRD architecture. CellMol Life Sci 2013, 70:3513-3524.

49. Jørgensen S, Elvers I, Trelle MB, Menzel T, Eskildsen M,Jensen ON, Helleday T, Helin K, Sørensen CS: The histonemethyltransferase SET8 is required for S-phase progression. JCell Biol 2007, 179:1337-1345.


50. Liu B, Wang Z, Ghosh S, Zhou Z: Defective ATM-Kap-1-mediated chromatin remodeling impairs DNA repair andaccelerates senescence in progeria mouse model. Aging Cell2012, 12:316-318.

51.��

Ibrahim MX, Sayin VI, Akula MK, Liu M, Fong LG, Young SG,Bergo MO: Targeting isoprenylcysteine methylationameliorates disease in a mouse model of progeria. Science2013, 340:1330-1333.

This paper revealed the importance of ICMT and further illustrated the keyrole played by AKT-mTOR signaling in delaying senescence in HGPScells.

52.�

Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z, Jin G, Zheng B,Kennedy BK, Suh Y, Kaeberlein M, Tryggvason K, Zhou Z:Resveratrol rescues SIRT1-dependent adult stem cell declineand alleviates progeroid features in laminopathy-basedprogeria. Cell Metabol 2012, 16:738-750.

This work illustrated the underlying mechanism of resveratrol’s function indelaying senescence.

53. Kubben N, Adriaens M, Meuleman W, Voncken JW, VanSteensel B, Misteli T: Mapping of lamin A-and progerin-interacting genome regions. Chromosoma 2012, 121:447-464.

54.�

Chen CY, Chi YH, Mutalif RA, Starost MF, Myers TG, Anderson SA,Stewart CL, Jeang KT: Accumulation of the inner nuclearenvelope protein sun1 is pathogenic in progeric anddystrophic laminopathies. Cell 2012, 149:565-577.

This paper revealed the pathogenesis of SUN1 protein accumulation inHGPS conditions and nuclear defects were rescued upon SUN1 reduc-tion delaying senescence.

55. Liang L, Zhang H, Gu X: Homozygous LMNA mutation R527C inatypical Hutchinson–Gilford progeria syndrome: evidence forautosomal recessive inheritance. Acta Paediatr 2009, 98:1365-1368.

56.�

Xiong Z, Lu Y, Xue J, Luo S, Xu X, Zhang L, Peng H, Li W, Chen D,Hu Z, Xia K: Hutchinson–Gilford progeria syndromeaccompanied by severe skeletal abnormalities in two Chinesesiblings: two case reports. J Med Case Rep 2013, 7:63.

This report identified another point mutation in LMNA gene causing HGPSand claimed that this particular mutation could be inherited in an auto-somal recessive manner.

57. Plasilova M, Chattopadhyay C, Ghosh A, Wenzel F, Demougin P,Noppen C, Schaub N, Szinnai G, Terracianno L, Heinimann K:Discordant gene expression signatures and relatedphenotypic differences in lamin A-and A/C-relatedHutchinson–Gilford progeria syndrome (HGPS). PLoS One2011, 6:e21433.

58. Reunert J, Wentzell R, Walter M, Jakubiczka S, Zenker M, Brune T,Rust T, Marquardt T: Neonatal progeria: increased ratio ofprogerin to lamin A leads to progeria of the newborn. Eur JHum Genet 2012, 20:933-937.

59. Carboni N, Politano L, Floris M, Mateddu A, Solla E, Olla S,Maggi L, Antoneitta MM, Piras R, Cocco E: Overlappingsyndromes in laminopathies: a meta-analysis of the reportedliterature. Acta Myol 2013, 32:7.

60. Schreiber KH, Kennedy BK: When lamins go bad: nuclearstructure and disease. Cell 2013, 152:1365-1375.































































































genetics of aging, progeria and lamin disorders

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