AG06917

AG06917 Fibroblast from Skin, Arm

Description:

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

Affected:

Yes

Sex:

Male

Age:

3 YR (At Sampling)

Overview

Repository

NIA Aging Cell Culture Repository

Subcollection

Heritable Diseases

Biopsy Source

Arm

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Untransformed

Sample Source

Fibroblast from Skin, Arm

Race

White

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Donor displayed classical signs of progeria including growth retardation; thin skin; a thin, beak-like nose; deficiency of subcutaneous tissue; small clavicles and thin, underdeveloped nails. His parents and 12 sibs are unaffected. Fibroblast cultures from the parents are AG06298 and AG06299. The biopsy for AG06917 was taken ante-mortem from skin of the anterior forearm. The culture was initiated on 9/6/73 using explants of minced tissue. The cell morphology is fibroblast-like. The karyotype is 46,XY; normal diploid male. Culture was frozen at PDL 34. 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

4.38

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

URACIL DNA GLYCOSYLASE

Seal et al (Proc Natl Acad Sci USA 85:2339-2343, 1988) reported that monoclonal antibody, 40.10.09 to normal uracil DNA glycosylase had normal immunoreactivity with the uracil DNA glycosylase from this cell culture. In contrast, the antibody did not recognize or inhibit the native enzyme from five different Bloom syndrome cultures.

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

Bramwell LR, Harries LW, Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes GeroScience: 2023

PubMed ID: 37751047

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

Maynard S, Hall A, Galanos P, Rizza S, Yamamoto T, Gram HH, Munk SHN, Shoaib M, Sørensen CS, Bohr VA, Lerdrup M, Maya-Mendoza A, Bartek J, Lamin A/C impairments cause mitochondrial dysfunction by attenuating PGC1a and the NAMPT-NAD+ pathway Nucleic acids research50:9948-9965 2022

PubMed ID: 36099415

Fafián-Labora JA, Rodríguez-Navarro JA, O'Loghlen A, Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage Cell metabolism50:9948-9965 2020

PubMed ID: 32574561

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 communications50:9948-9965 2020

PubMed ID: 32115145

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 reports50:e49680 2019

PubMed ID: 32815283

Mu X, Tseng C, Hambright WS, Matre P, Lin CY, Chanda P, Chen W, Gu J, Ravuri S, Cui Y, Zhong L, Cooke JP, Niedernhofer LJ, Robbins PD, Huard J, Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson-Gilford Progeria Syndrome Aging cell50:e49680 2019

PubMed ID: 32710480

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

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

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

Park WY, Hwang CI, Kang MJ, Seo JY, Chung JH, Kim YS, Lee JH, Kim H, Kim KA, Yoo HJ, Seo JS, Gene profile of replicative senescence is different from progeria or elderly donor. Biochem Biophys Res Commun282(4):934-9 2001

PubMed ID: 11352641

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

Seal G, Brech K, Karp SJ, Cool BL, Sirover MA, Immunological lesions in human uracil DNA glycosylase: association with Bloom syndrome. Proc Natl Acad Sci U S A85:2339-43 1988

PubMed ID: 3353381

Sephel GC, Sturrock A, Giro MG, Davidson JM, Increased elastin production by progeria skin fibroblasts is controlled by the steady-state levels of elastin mRNA. J Invest Dermatol90:643-7 1988

PubMed ID: 3361140

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

PubMed ID: 1128606