The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin.
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.
McClintock
Dayle
D
Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
Ratner
Desiree
D
Lokuge
Meepa
M
Owens
David M
DM
Gordon
Leslie B
LB
Collins
Francis S
FS
Djabali
Karima
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism*; D016922:Cellular Senescence / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000276:immunology; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000276:immunology; D012867:Skin / Q000473:pathology*
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D017931:DNA Primers; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A