AG11498

AG11498 Fibroblast from Skin, Thigh

Description:

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

Affected:

Yes

Sex:

Male

Age:

14 YR (At Sampling)

Overview

Repository

NIA Aging Cell Culture Repository

Subcollection

Heritable Diseases

Biopsy Source

Thigh

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

Fibroblast from Skin, Thigh

Race

Black/African American

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Donor showed typical appearance including loss of subcutaneous fat, alopecia, osteoarthritis, and a grade II/VI systolic heart murmur. The biopsy was taken ante-mortem on 4/26/91 from skin of the anterior midupper right thigh. The culture was initiated on 4/30/91 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)]. Same subject as AG28340 (stem Cell).

Characterizations

PDL at Freeze

5.4

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

Kim J, Hwang Y, Kim S, Chang Y, Kim Y, Kwon Y, Kim J, Transcriptional activation of endogenous Oct4 via the CRISPR/dCas9 activator ameliorates Hutchinson-Gilford progeria syndrome in mice Aging cell:e13825 2023

PubMed ID: 36964992

Della Valle F, Reddy P, Yamamoto M, Liu P, Saera-Vila A, Bensaddek D, Zhang H, Prieto Martinez J, Abassi L, Celii M, Ocampo A, Nuñez Delicado E, Mangiavacchi A, Aiese Cigliano R, Rodriguez Esteban C, Horvath S, Izpisua Belmonte JC, Orlando V, LINE-1 RNA causes heterochromatin erosion and is a target for amelioration of senescent phenotypes in progeroid syndromes Science translational medicine14:eabl6057 2022

PubMed ID: 35947677

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

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

Dworak N, Makosa D, Chatterjee M, Jividen K, Yang CS, Snow C, Simke WC, Johnson IG, Kelley JB, Paschal BM, A nuclear lamina-chromatin-Ran GTPase axis modulates nuclear import and DNA damage signaling Aging Cell4:5 2018

PubMed ID: 30565836

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 Signaling11:5 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

Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S, Taldone T, Fusaki N, Tomishima MJ, Krainc D, Milner TA, Rossi DJ, Studer L., Human iPSC-Based Modeling of Late-Onset Disease via Progerin-Induced Aging. Cell Stem Cell.13(6):691-705 2013

PubMed ID: 24315443

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

Ragnauth CD, Warren DT, Liu Y, McNair R, Tajsic T, Figg N, Shroff R, Skepper J, Shanahan CM, Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging Circulation121:2200-10 2010

PubMed ID: 20458013

Zhang J, Lian Q, Zhu G, Zhou F, Sui L, Tan C, Mutalif RA, Navasankari R, Zhang Y, Tse HF, Stewart CL, Colman A, A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects Cell stem cell8:31-45 2010

PubMed ID: 21185252

Britt-Compton B, Wyllie F, Rowson J, Capper R, Jones RE, Baird DM, Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells Biogerontology8:31-45 2008

PubMed ID: 19214769

Decker ML, Chavez E, Vulto I, Lansdorp PM, Telomere length in Hutchinson-Gilford progeria syndrome Mechanisms of ageing and development130:377-83 2008

PubMed ID: 19428457

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

Scaffidi P, Misteli T, Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing Nature cell biology28:882-9 2007

PubMed ID: 18311132

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

Glynn MW, Glover TW, Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition Human molecular genetics14:2959-69 2005

PubMed ID: 16126733

Scaffidi P, Misteli T, Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med11(4):440-5 2005

PubMed ID: 15750600

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

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

Hasty MF, Vann WF Jr, Progeria in a pediatric dental patient: literature review and case report. Pediatr Dent10:314-9 1988

PubMed ID: 2978820