LMNA
|
Lamin-A/C |
Fibroblasts from FPLD2 subjects harboring the pathogenic variants in the LMNA genes (p.D47Y, p.L92F, p.L387V, p. R399H, p.L421P, and p. R482W) |
Oxidative stress, mitochondrial dysfunction, cell cycle arrest, and premature senescence. |
Partial loss of sWAT. |
(Caron et al., 2007Caron M, Auclair M, Donadille B, Béréziat V, Guerci B, Laville M, Narbonne H, Bodemer C, Lascols O, Capeau J et al. (2007) Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence. Cell Death Differ 14:1759-1767.) |
LMNA
|
Lamin-A/C |
Smooth Muscle Cells (SMCs) and fibroblasts from HGPS individuals carrying the pathogenic variant p.G608G. |
PARP-1 suppression. Frequent DSBs, persistent activation of ATM and ATR. Higher levels of p-Chk-1, p-Chk-2, and p-p53. Mitochondrial dysfunction and NFE2L2 sequestration by progerin. |
- |
(Liu et al., 2006Liu Y, Rusinol A, Sinensky M, Wang Y and Zou Y (2006) DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A. J Cell Sci 119:4644-4649.; Zhang et al., 2014Zhang H, Xiong ZM and Cao K (2014) Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1. Proc Natl Acad Sci U S A 111:E2261-E2270.; Kubben et al., 2016Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH and Misteli T (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell 165:1361-1374.) |
LMNA
|
Lamin-A/C |
Fibroblasts from MADA individuals harboring the pathogenic variant p.R527H in the LMNA gene. |
High levels of chromosome aberrations. Increased phosphorylated ATM-S1981 foci and γ-H2AX, and p53 after IR treatment. |
- |
(Di Masi et al., 2008Di Masi A, D’Apice MR, Ricordy R, Tanzarella C and Novelli G (2008) The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation. Cell Cycle 7:2030-2037.) |
LMNA and ZMPSTE24
|
Lamin-A/C and Zinc metalloproteinase STE24 homolog |
Zmpste24-/- MEFs and HGPS fibroblasts carrying the pathogenic variant p.G608G. |
High 53BP1 foci and increased protein levels of γH2AX and p-chk1. High sensibilization of Zmpste24 -/- MEFs to DNA-damage agents. Delayed γH2AX/53BP1 co-localization. Higher DNA damage levels and decreased Rad51 foci formation. |
- |
(Liu et al., 2005Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ et al. (2005) Genomic instability in laminopathy-based premature aging. Nat Med 11:780-785.) |
ERCC8 and XPA
|
CSA and XPA |
CX (Csa -/- /Xpa-/- ) mice with similar aspects of human progeria. |
Increase in FAO/OXPHOS, decline of NAD+ and ATP levels, and increased levels of pAMPK due to PARP-1 activity. |
Progressive loss of sWAT, low levels of TGs, and glucose. Decline in mature adipocyte size without crown-like (CL) structures, decreased sWAT and perigonadal WAT. Low levels of glucose, insulin, HOMA-IR, TGs, and leptin levels. |
(Brace et al., 2013Brace LE, Vose SC, Vargas DF, Zhao S, Wang XP and Mitchell JR (2013) Lifespan extension by dietary intervention in a mouse model of Cockayne syndrome uncouples early postnatal development from segmental progeria. Aging Cell 12:1144-1147.; Brace et al., 2016Brace LE, Vose SC, Stanya K, Gathungu RM, Marur VR, Longchamp A, Treviño-Villarreal H, Mejia P, Vargas D, Inouye K et al. (2016) Increased oxidative phosphorylation in response to acute and chronic DNA damage. NPJ Aging Mech Dis 2:16022.) |
ERCC6
and XPA
|
CSB and XPA |
Csbm/m /Xpa-/- mice mimic the human progeroid CS syndrome. |
Upregulation of genes associated with fatty acids synthesis and genes encoding antioxidant enzymes in the liver. Downregulation of genes involved in glycolysis, TCA, and OXPHOS. |
sWAT loss and upregulation of Lepr and Pparg. Increased levels of TGs and glycogen accumulation. Low levels of glucose and IGF. |
(Van Der Pluijm et al., 2007Van Der Pluijm I, Garinis GA, Brandt RMC, Gorgels TGMF, Wijnhoven SW, Diderich KEM, De Wit J, Mitchell JR, Van Oostrom C, Beems R et al. (2007) Impaired genome maintenance suppresses the growth hormone-insulin-like growth factor 1 axis in mice with cockayne syndrome. PLoS Biol 5:e2.) |
ERCC6
|
CSB and XPC |
Csbm/m /Xpc-/- mice mimic the human progeroid CS syndrome. |
- |
sWAT loss. |
(Van Der Pluijm et al., 2007Van Der Pluijm I, Garinis GA, Brandt RMC, Gorgels TGMF, Wijnhoven SW, Diderich KEM, De Wit J, Mitchell JR, Van Oostrom C, Beems R et al. (2007) Impaired genome maintenance suppresses the growth hormone-insulin-like growth factor 1 axis in mice with cockayne syndrome. PLoS Biol 5:e2.) |
ERCC1 and ERCC4
|
Ercc1 and XPF |
Ercc1-/- mice and XFE (XPF-ERCC1) fibroblasts from a subject harboring c.458 G>C in the ERCC4 gene. |
Sensitivity to oxidative stress. Upregulation of genes associated with fatty acids synthesis and genes encoding antioxidant enzymes in the liver. |
sWAT loss and upregulation of Lepr and Pparg. Low levels of glucose, insulin, and IGF. |
(Niedernhofer et al., 2006Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, Van Leeuwen W et al. (2006) A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444:1038-1043.) |
ERCC1
|
ERCC1 |
Ercc1-/- fat depots from mice |
Persistent DNA damage. |
sWAT loss. |
(Karakasilioti et al., 2013Karakasilioti I, Kamileri I, Chatzinikolaou G, Kosteas T, Vergadi E, Robinson AR, Tsamardinos I, Rozgaja TA, Siakouli S, Tsatsanis C et al. (2013) DNA damage triggers a chronic auto-inflammatory response leading to fat depletion in NER progeria. Cell Metab 18:403-415.) |
BANF1
|
Barrier-to-autointegration factor |
Skin fibroblasts from NGPS subjects harboring c.34 G>A (p.A12T) in the BANF1 gene. |
Defective PARP-1 activity and disrupted repair of oxidized DNA lesions. |
Generalized lipodystrophy. |
(Bolderson et al., 2019Bolderson E, Burgess JT, Li J, Gandhi NS, Boucher D, Croft L V., Beard S, Plowman JJ, Suraweera A, Adams MN et al. (2019) Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage. Nat Commun 10:5501.) |
RECQL2
|
DNA helicase, RECQ protein-like 2 |
WRN-/- human pluripotent stem cells (hPSCs) that were differentiated in adipocyte precursors (APs) |
Reduced cell proliferation, shorter telomeres, and senescence. |
Attenuated differentiation of WRN -/- APs to mature adipocytes and low adiponectin secretion. Low expression levels of FABP4, CEBPA, GLUT4, and ADIPOQ mRNAs in WRN -/- APs. |
(Goh et al., 2020Goh KJ, Chen JH, Rocha N and Semple RK (2020) Human pluripotent stem cell-based models suggest preadipocyte senescence as a possible cause of metabolic complications of Werner and Bloom Syndromes. Sci Rep 10:7490.) |
RECQL3
|
DNA helicase, RECQ protein-like 3 |
BLM-/- human pluripotent stem cells (hPSCs) that were differentiated in adipocyte precursors |
Reduced cell proliferation, shorter telomeres, and senescence. |
Attenuated differentiation of BLM -/- APs to mature adipocytes. Low expression levels of FABP4, CEBPA, GLUT4, and ADIPOQ mRNAs in WRN -/- APs. |
(Goh et al., 2020Goh KJ, Chen JH, Rocha N and Semple RK (2020) Human pluripotent stem cell-based models suggest preadipocyte senescence as a possible cause of metabolic complications of Werner and Bloom Syndromes. Sci Rep 10:7490.) |
POLR3A
|
RNA Polymerase III, subunit A |
WRS fibroblasts carrying the pathogenic variant c.3772_3773delCT in the POLR3A gene. |
Senescent cells. Increased levels of γH2AX and p53. |
- |
(Báez-Becerra et al., 2020Báez-Becerra CT, Valencia-Rincón E, Velásquez-Méndez K, Ramírez-Suárez NJ, Guevara C, Sandoval-Hernandez A, Arboleda-Bustos CE, Olivos-Cisneros L, Gutiérrez-Ospina G, Arboleda H et al. (2020) Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mech Ageing Dev 192:111360.) |
SPRTN
|
DNA-Dependent Metalloprotease Spartan |
SPRTN-depleted U2OS cells, RJALS fibroblasts, Sprtn F/- MEFs, SPRTN-KO MEFs, and RJALS lymphoblastoid cells. |
Increased accumulation of γH2AX and 53BP1 after CPT treatment in SPRTN-depleted U2OS cells transfected with the mutant p.Tyr117Cys or ∆C-TER SPRTN. Severe growth defect and increased levels of DSBs in patient fibroblasts. Increased numbers of 53BP1 nuclear bodies in Sprtn F/- MEFs. High sensitivity of lymphoblastoid cells derived from RJALS and SPRTN-KO MEFs to DPCs-inductor agents. |
- |
(Maskey et al., 2014Maskey RS, Kim MS, Baker DJ, Childs B, Malureanu LA, Jeganathan KB, Machida Y, Van Deursen JM and Machida YJ (2014) Spartan deficiency causes genomic instability and progeroid phenotypes. Nat Commun 5:5744.; Lessel et al., 2014Lessel D, Vaz B, Halder S, Lockhart PJ, Marinovic-Terzic I, Lopez-Mosqueda J, Philipp M, Sim JCH, Smith KR, Oehler J et al. (2014) Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet 46:1239-1244.; Lopez-Mosqueda et al., 2016Lopez-Mosqueda J, Maddi K, Prgomet S, Kalayil S, Marinovic-Terzic I, Terzic J and Dikic I (2016) SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks. Elife 5:e21491.) |
POLD1
|
DNA polymerase delta 1 |
Individuals with MDPL harboring the heterozygous single codon deletion c.1812-1814delCTC (p.Ser605del) in the POLD1 gene. |
The catalytic subunit of POLD1 was affected, resulting in no detectable polymerase activity. |
Progressive lack of sWAT in childhood, increased visceral adipose tissue (vWAT), and insulin resistance. Fibrosis in sWAT and high levels of genes from ECM, such as TGFB1 andFN1. |
(Shastry et al., 2010Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS, Novelli G, Kroiss M and Garg A (2010) A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism. J Clin Endocrinol Metab 95:E192-7.; Weedon et al., 2013Weedon MN, Ellard S, Prindle MJ, Caswell R, Allen HL, Oram R, Godbole K, Yajnik CS, Sbraccia P, Novelli G et al. (2013) An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 45:947-950.; Reinier et al., 2015Reinier F, Zoledziewska M, Hanna D, Smith JD, Valentini M, Zara I, Berutti R, Sanna S, Oppo M, Cusano R et al. (2015) Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies. Metabolism 64:1530-1540.; Okada et al., 2017Okada A, Kohmoto T, Naruto T, Yokota I, Kotani Y, Shimada A, Miyamoto Y, Takahashi R, Goji A, Masuda K et al. (2017) The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection. Hum Genome Var 4:17031.; Sasaki et al., 2018Sasaki H, Yanagi K, Ugi S, Kobayashi K, Ohkubo K, Tajiri Y, Maegawa H, Kashiwagi A and Kaname T (2018) Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene. Endocr J65:227-238.; Wang et al., 2018Wang LR, Radonjic A, Dilliott AA, McIntyre AD and Hegele RA (2018) A de novo POLD1 mutation associated with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome in a family with Werner syndrome. J Investig Med High Impact Case Rep 6:2324709618786770.; Yu et al., 2021Yu PT, Luk HM, Mok MT and Lo FI (2021) Evolving clinical manifestations of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome: From infancy to adulthood in a 31-year-old woman. Am J Med Genet A 185:995-998.) |
POLD1
|
DNA polymerase delta 1 |
Individuals with MDPL harboring a heterozygous variant in the exonuclease domain of the POLD1 gene (p.Arg507Cys) |
- |
Lipoatrophy in almost all body, but not in mechanic WAT. |
(Pelosini et al., 2014Pelosini C, Martinelli S, Ceccarini G, Magno S, Barone I, Basolo A, Fierabracci P, Vitti P, Maffei M and Santini F (2014) Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome. Metabolism 63:1385-1389.) |
POLD1
|
DNA polymerase delta 1 |
Individuals with MDPL harboring heterozygous variants in the ZNF1 domain of the POLD1 gene (c.3199 G>A; p.Glu1067Lys and c.3209 T>A; p.Ile1070Asn). |
- |
Generalized loss of sWAT and progeroid features in a patient harboring p.Ile1070Asn but not in the patients harboring p.Glu1067Lys, which had IR, elevated CK levels, and proteinuria. |
(Ajluni et al., 2017Ajluni N, Meral R, Neidert AH, Brady GF, Buras E, McKenna B, DiPaola F, Chenevert TL, Horowitz JF, Buggs-Saxton C et al. (2017) Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort. Clin Endocrinol (Oxf) 86:698-707.; Elouej et al., 2017Elouej S, Beleza-Meireles A, Caswell R, Colclough K, Ellard S, Desvignes JP, Béroud C, Lévy N, Mohammed S and De Sandre-Giovannoli A (2017) Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL). Metabolism71:213-225.) |
POLD1
|
DNA polymerase delta 1 |
HDFs from MDPL individuals harboring the heterozygous single codon deletion c.1812-1814delCTC (p.Ser605del) in the POLD1 gene. |
Nuclear envelope abnormalities, intranuclear accumulation of prelamin-A, high levels of micronuclei, cellular senescence, and growth decline. High levels of γH2AX foci after cisplatin-induced DSBs. |
Diminished sWAT in limbs and increased AT in neck, abdomen, mesenteric regions, and retroperitoneal space. Progeroid features. |
(Fiorillo et al., 2018Fiorillo C, D’Apice MR, Trucco F, Murdocca M, Spitalieri P, Assereto S, Baratto S, Morcaldi G, Minetti C, Sangiuolo F et al. (2018) Characterization of MDPL fibroblasts carrying the recurrent p.Ser605del mutation in POLD1 gene. DNA Cell Biol 37:1061-1067.; Murdocca et al., 2021Murdocca M, Spitalieri P, Masi CD, Udroiu I, Marinaccio J, Sanchez M, Talarico RV, Fiorillo C, D’Adamo M, Sbraccia P et al. (2021) Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity. Aging (Albany NY) 13:4926-4945.) |
BSCL2
|
Seipin |
Leukocytes from CGL2 subjects harboring c.325dupA in the BSCL2 gene. |
High levels of oxidative stress and mitochondrial DNA damage. Upregulation of NFE2L2, APEX1, OGG1, and α-OGG1. |
Severe loss of sWAT, Low HDL-c, low adiponectin and leptin levels, high levels of triglycerides in plasma |
(Craveiro Sarmento et al., 2020Craveiro Sarmento AS, Gomes Lima J, de Souza Timoteo AR, Galvão Ururahy MA, Antunes de Araújo A, Carvalho Vasconcelos R, Cândido Dantas VK, Fassarella Agnez-Lima L and Araújo de Melo Campos JT (2020) Changes in redox and endoplasmic reticulum homeostasis are related to congenital generalized lipodystrophy type 2. Biochim Biophys Acta Mol Cell Biol Lipids1865:158610.) |
CAV1 and AGPAT2
|
Caveolin-1 and 1-AGPAT 2 |
Whole blood from a subject harboring the heterozygous pathogenic variants c.479_480delTT (p.Phe160X) in the CAV1 and c.51_52insGTC in the AGPAT2 gene. |
Downregulation of Fanconi anemia pathway, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). Downregulation of AGPAT2, RECQL4, and WRN genes. Upregulation of the ATM gene. |
Severe loss of sWAT. High levels of triglycerides in infancy. Low levels of caveolin-1 protein. |
(Schrauwen et al., 2015Schrauwen I, Szelinger S, Siniard AL, Kurdoglu A, Corneveaux JJ, Malenica I, Richholt R, Van Camp G, De Both M, Swaminathan S et al. (2015) A frame-shift mutation in CAV1 is associated with a severe neonatal progeroid and lipodystrophy syndrome. PLoS One 10:e0131797.) |