Abstract
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.
Highlights
Lamins of the A- and B-type are intermediate filament proteins that constitute major components of the nuclear lamina, a filamentous meshwork forming an interface between the inner nuclear membrane and the chromatin [1]
Using the human skin as our model system, we investigated whether progerin is expressed in the skin of unaffected individuals. 150 skin biopsies from newborn foreskins and from unaffected individuals, including equal numbers of females and males ranging in age from 22 to 97 years were collected from the Dermatology Clinic at Columbia University
While a progerin-positive signal was sporadically detected in keratinocytes from the interfollicular dermis, no signal was detected in the different epidermal appendages and vasculature system regardless of body site or age of the donor sample under our experimental conditions. These data show for the first time that sporadic use of the cryptic splice site in exon 11 of LMNA occurs in vivo in normal cells, that site is much more active in HGPS cells carrying the LMNA G608G mutation
Summary
Lamins of the A- and B-type are intermediate filament proteins that constitute major components of the nuclear lamina, a filamentous meshwork forming an interface between the inner nuclear membrane and the chromatin [1]. Lamins A and C, the major isoforms of A-type lamins, are expressed in all differentiated vertebrate cells [2] and are translated from alternatively spliced transcripts of the LMNA gene. Lamin A and lamin B are modified at their carboxyl-terminal –CAAX box through a series of post-translational modifications. The modifications include, successively, farnesylation of the cysteine in the C-terminal CaaX motif (C, cysteine; a, aliphatic; X, any amino acid), followed by a proteolytic cleavage of the aaX-terminal tripeptide, and by methylation of the farnesylated cysteine [13]. While B-type lamins remain permanently farnesylated, prelamin A (the precursor of mature lamin A) undergoes a second cleavage of the remaining 15 C-terminal residues (aa 647–661) to give rise to the mature lamin A, losing its farnesyl modification [13,14]. The enzyme responsible for these sequential proteolytic cleavages is the zinc metalloproteinase ZMSPTE24, for which lamin A is the only known substrate in mammals [15]
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