AG11513

AG11513 Fibroblast from Skin, Leg

Description:

HUTCHINSON-GILFORD PROGERIA SYNDROME; HGPS
LAMIN A/C; LMNA

Affected:

Yes

Sex:

Female

Age:

8 YR (At Sampling)

Overview

Repository

NIA Aging Cell Culture Repository

Subcollection

Heritable Diseases

Biopsy Source

Leg

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

Fibroblast from Skin, Leg

Race

White

Relation to Proband

proband

Confirmation

Clinical summary/Case history

ISCN

46,XX,inv trp(11)(pter->q25::q25->q21::q21->qter)[5]/46,XX[19].arr(1-22,X)x2

Species

Homo sapiens

Common Name

Human

Remarks

Donor showed typical appearance including alopecia and bilateral symmetrical coxa valga. The biopsy was taken ante-mortem on 5/09/91 from skin of the anterior upper leg. The culture was initiated on 5/10/91 using explants of minced skin tissue. The cell morphology is fibroblast-like. Donor subject has a de novo single base substitution, a C>T change at nucleotide 2036 (2036C>T), which results in a silent change at codon 608 [Gly608Gly (G608G)] in exon 11 of the Lamin A gene (LMNA). This substitution creates an exonic consensus splice donor sequence and results in activation of a cryptic splice site which in turn causes skipping of 150 bp of the LMNA mRNA leading to the deletion of 50 amino acids from the protein. This altered LMNA protein was detected on western blots [Eriksson et al., Nature 423:293 (2003)].

Characterizations

PDL at Freeze

5.87

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis

Gene

LMNA

Chromosomal Location

1q21.2

Allelic Variant 1

150330.0022; HUTCHINSON-GILFORD PROGERIA SYNDROME

Identified Mutation

GLY608GLY; Description: In 18 of 20 patients with classic Hutchinson-Gilford progeria syndrome (176670), Eriksson et al. [Nature 423: 293 (2003)] found an identical de novo single-base substitution, a C-to-T change resulting in a silent gly-to-gly mutation at codon 608 (G608G) within exon 11 of the LMNA gene. This substitution created an exonic consensus splice donor sequence and resulted in activation of a cryptic splice site and deletion of 50 basepairs of prelamin A. This mutation was not identified in any of the 16 parents available for testing.

Phenotypic Data

Remarks

Publications

Catarinella G, Nicoletti C, Bracaglia A, Procopio P, Salvatori I, Taggi M, Valle C, Ferri A, Canipari R, Puri PL, Latella L, SerpinE1 drives a cell-autonomous pathogenic signaling in Hutchinson-Gilford progeria syndrome Cell death & disease13:737 2022

PubMed ID: 36028501

Frankel D, Delecourt V, Novoa-Del-Toro EM, Robin JD, Airault C, Bartoli C, Carabalona A, Perrin S, Mazaleyrat K, De Sandre-Giovannoli A, Magdinier F, Baudot A, Lévy N, Kaspi E, Roll P, miR-376a-3p and miR-376b-3p overexpression in Hutchinson-Gilford progeria fibroblasts inhibits cell proliferation and induces premature senescence iScience25:103757 2021

PubMed ID: 35118365

Kychygina A, Dall'Osto M, Allen JAM, Cadoret JC, Piras V, Pickett HA, Crabbe L, Progerin impairs 3D genome organization and induces fragile telomeres by limiting the dNTP pools Scientific reports11:13195 2021

PubMed ID: 34162976

Arii J, Maeda F, Maruzuru Y, Koyanagi N, Kato A, Mori Y, Kawaguchi Y, ESCRT-III controls nuclear envelope deformation induced by progerin Scientific reports10:18877 2020

PubMed ID: 33139753

Kang SM, Yoon MH, Ahn J, Kim JE, Kim SY, Kang SY, Joo J, Park S, Cho JH, Woo TG, Oh AY, Chung KJ, An SY, Hwang TS, Lee SY, Kim JS, Ha NC, Song GY, Park BJ, Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome Communications biology4:5 2020

PubMed ID: 33398110

Lee J, Bignone PA, Coles LS, Liu Y, Snyder E, Larocca D, Induced pluripotency and spontaneous reversal of cellular aging in supercentenarian donor cells Biochemical and biophysical research communications4:5 2020

PubMed ID: 32115145

Chen WM, Chiang JC, Lin YC, Lin YN, Chuang PY, Chang YC, Chen CC, Wu KY, Hsieh JC, Chen SK, Huang WP, Chen BPC, Lee H, Lysophosphatidic acid receptor LPA Aging cell4:e13064 2019

PubMed ID: 31714004

Fan JR, You LR, Wang WJ, Huang WS, Chu CT, Chi YH, Chen HC, Lamin A-mediated nuclear lamina integrity is required for proper ciliogenesis EMBO reports4:e49680 2019

PubMed ID: 32815283

Lan YY, Heather JM, Eisenhaure T, Garris CS, Lieb D, Raychowdhury R, Hacohen N, Extranuclear DNA accumulates in aged cells and contributes to senescence and inflammation Aging cell4:e12901 2018

PubMed ID: 30706626

Larrieu D1, Viré E2, Robson S2, Breusegem SY2, Kouzarides T2, Jackson SP1., Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway Science Signaling11:e12901 2018

PubMed ID: 29970603

Li Y, Zhou G, Bruno IG, Zhang N, Sho S, Tedone E, Lai TP, Cooke JP, Shay JW, Transient introduction of human telomerase mRNA improves hallmarks of progeria cells Aging cell18:e12979 2018

PubMed ID: 31152494

Chen CY, Chi YH, Mutalif RA, Starost MF, Myers TG, Anderson SA, Stewart CL, Jeang KT., Accumulation of inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Cell149:565-77 2012

PubMed ID: 22541428

Nissan X, Blondel S, Navarro C, Maury Y, Denis C, Girard M, Martinat C, De Sandre-Giovannoli A, Levy N, Peschanski M, Unique preservation of neural cells in Hutchinson- Gilford progeria syndrome is due to the expression of the neural-specific miR-9 microRNA Cell reports2:1-9 2011

PubMed ID: 22840390

Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Löbrich M, Jeggo PA, ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin Molecular cell31:167-77 2007

PubMed ID: 18657500

Moulson CL, Fong LG, Gardner JM, Farber EA, Go G, Passariello A, Grange DK, Young SG, Miner JH, Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes Human mutation28:882-9 2007

PubMed ID: 17469202

Liu Y, Rusinol A, Sinensky M, Wang Y, Zou Y, DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A Journal of cell science119:4644-9 2006

PubMed ID: 17062639

Capell BC, Erdos MR, Madigan JP, Fiordalisi JJ, Varga R, Conneely KN, Gordon LB, Der CJ, Cox AD, Collins FS, Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome Proceedings of the National Academy of Sciences of the United States of America102:12879-84 2005

PubMed ID: 16129833

Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL, Miner JH, Young SG, Fong LG, Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes Proceedings of the National Academy of Sciences of the United States of America102:12873-8 2005

PubMed ID: 16129834

Csoka AB, English SB, Simkevich CP, Ginzinger DG, Butte AJ, Schatten GP, Rothman FG, Sedivy JM, Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell3(4):235-43 2004

PubMed ID: 15268757

Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, Collins FS, Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A101(24):8963-8 2004

PubMed ID: 15184648

Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS, Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature423(6937):293-8 2003

PubMed ID: 12714972