AG06297

AG06297 Fibroblast from Skin, Thigh

Description:

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

Affected:

Yes

Sex:

Male

Age:

8 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

White

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

The donor had classic features of progeria and died at age 14 years of congestive heart failure. Autopsy revealed severe coronary-vascular disease. The biopsy was taken ante-mortem on 1/11/72 from skin on the anterior thigh region. The culture was initiated using explants of minced skin tissue. The cell morphology is fibroblast-like. The karyotype is 46,XY; normal diploid male. Culture is frozen at PDL 33 and has a maximum lifespan of 40 PD. 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)]. The legacy karyotype description shown in this Remark may not be representative of the current available product.

Characterizations

PDL at Freeze

4.45

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

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

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

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

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

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 communications11:13195 2020

PubMed ID: 32115145

Puttaraju M, Jackson M, Klein S, Shilo A, Bennett CF, Gordon L, Rigo F, Misteli T, Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson-Gilford progeria syndrome Nature medicine27:526-535 2020

PubMed ID: 33707772

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 reports27:e49680 2019

PubMed ID: 32815283

Hamczyk MR, Villa-Bellosta R, Quesada V, Gonzalo P, Vidak S, Nevado RM, Andrés-Manzano MJ, Misteli T, López-Otín C, Andrés V, Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells EMBO molecular medicine11:e49680 2019

PubMed ID: 30862662

Bikkul MU1, Faragher RGA2, Worthington G1, Meinke P3,4, Kerr ARW4, Sammy A1, Riyahi K1, Horton D1, Schirmer EC4, Hubank M5, Kill IR1, Anderson RM1, Slijepcevic P1, Makarov E1, Bridger JM1., Telomere elongation through hTERT immortalisation leads to chromosome repositioning in control cells and genomic instability in Hutchinson-Gilford Progeria syndrome fibroblasts, expressing a novel SUN1 isoform Genes Chromosomes Cancer11:e49680 2018

PubMed ID: 30474255

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

Rivera-Torres J, Acín-Perez R, Cabezas-Sánchez P, Osorio FG, Gonzalez-Gómez C, Megias D, Cámara C, López-Otín C, Enríquez JA, Luque-García JL, Andrés V., Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture. J Proteomics.91C:466-477 2013

PubMed ID: 23969228

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

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

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

Bridger JM, Kill IR, Aging of Hutchinson-Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis. Exp Gerontol39(5):717-24 2004

PubMed ID: 15130666

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 of telomerase. Exp Gerontol39(4):461-7 2004

PubMed ID: 15050279

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

Ly DH, Lockhart DJ, Lerner RA, Schultz PG, Mitotic misregulation and human aging. Science287(5462):2486-92 2000

PubMed ID: 10741968

Winkles JA, O'Connor ML, Friesel R, Altered regulation of platelet-derived growth factor A-chain and c-fos gene expression in senescent progeria fibroblasts. J Cell Physiol144:313-25 1990

PubMed ID: 2166059

Goldstein S, Moerman E, Heat-labile enzymes in skin fibroblasts from subjects with progeria. N Engl J Med292:1305-9 1975

PubMed ID: 1128606