I. From Gene Editing to Aging‑Related Phenotypes: Why Choose LMNA?

Gene‑edited mice employ molecular‑biology, genetic and embryo‑manipulation techniques to precisely modify target genes, generating genetic‑altered animals with gene‑knockout (KO), gene‑knock‑in (KI), conditional knockout (cKO), point‑mutation or base‑editing modifications.

Compared with early research approaches that merely deliver exogenous genes into single‑cell lines, gene‑editing technology bridges “specific genes” and “intact living organisms”. It enables dynamic dissection of gene functions throughout development, senescence, tissue‑tissue crosstalk and disease progression. The technical toolkit has evolved from conventional transgenesis and embryonic‑stem‑cell targeting to mature workflows including CRISPR/Cas‑mediated base editing.

Morphological differences in nuclei between wild‑type and HGPS cells caused by intracellular progerin accumulation

For aging‑related research, selection of appropriate target genes is critical for model construction. The LMNA gene encodes lamin A/C, type‑A nuclear lamins located beneath the inner nuclear envelope. They sustain nuclear structural integrity and participate in chromatin organisation as well as mechanotransduction. Mutations in LMNA give rise to over 900 variants and a broad spectrum of laminopathy phenotypes, including mandibulo‑acral dysplasia (MAD), Emery‑Dreifuss muscular dystrophy (EDMD), and Hutchinson‑Gilford progeria syndrome (HGPS).

As a childhood progeroid disorder, HGPS has an average patient life expectancy of only 14.6 years. It serves as a natural “accelerated‑aging model” for mechanistic aging research. Accordingly, introducing disease‑causing LMNA mutations into mice via gene editing represents one of the most straightforward and phenotypically robust strategies to generate progeria mouse models.

The most prevalent pathogenic HGPS mutation is human LMNA c.1824C>T (p.G608G; the mouse homologous site is c.1827C>T, p.G609G). Rather than triggering a missense amino‑acid substitution, this mutation activates a cryptic splice‑donor site. This leads to aberrant splicing of pre‑lamin A mRNA, yielding a truncated protein termed progerin, with a 50‑amino‑acid deletion at its C‑terminus.

Progerin retains the C‑terminal CAAX farnesylation anchoring motif but loses the cleavage site for the ZMPSTE24 protease. Consequently, the farnesylated‑cysteine‑methyl ester moiety cannot be removed, and progerin remains persistently anchored to the inner nuclear membrane. Accumulating with age, progerin disrupts nuclear‑envelope stability, chromatin organisation and mechanotransduction, ultimately driving cellular senescence, tissue fibrosis, vasculopathy and multi‑organ functional decline. This well‑defined causal cascade — “single‑point mutation → protein truncation → nuclear‑architecture collapse → systemic aging” — makes LMNA an ideal target for validating gene‑edited aging animal models.

II. Representative LMNA‑Driven Progeria / Aging Mouse Models

1. Lamin A C1827T (Lmna^G609G) Point‑Mutation Mice

Endogenous mouse Lmna is edited by gene targeting or base editing to introduce the c.1827 C→T alteration, which drives progerin production from native mouse transcripts. Both heterozygous and homozygous animals exhibit accelerated‑aging hallmarks: alopecia, growth retardation, short stature, skeletal anomalies, impaired motor performance, lipodystrophy, chronic inflammation, organ fibrosis and vascular sclerosis.

This strain displays pronounced progeroid phenotypes and a shortened lifespan; homozygous mice frequently succumb at approximately 3‑4 months of age. It is one of the most widely cited mouse lines that closely recapitulate the full‑body clinical manifestations of human HGPS.

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2. Lmna^HG (Progerin‑Only) Mice

Truncations are introduced at the distal end of Lmna exon 11 plus adjacent intronic sequences. This allele exclusively expresses progerin and abolishes production of normal lamin A/C. Heterozygous Lmna^HG/+ mice show growth retardation, osteoporosis, hair loss, mandibular hypoplasia and reduced subcutaneous fat, with death occurring around 6‑7 months of age. Homozygous Lmna^HG/HG animals exhibit much more severe disease and early lethality.

This model lacks typical large‑vessel pathological lesions. Therefore it is suitable for investigations focused on bone, adipose tissue, skin and nuclear‑structure defects, but not for standalone studies on the cardiovascular causes of HGPS‑related mortality.

3. LMNA^G608G‑BAC Transgenic Mice

A 164 kb human bacterial artificial chromosome (BAC) carrying the human LMNA^G608G mutation is microinjected into mouse zygotes. Human‑mutant LMNA is expressed to generate progerin, while endogenous mouse Lmna remains intact.

Heterozygous animals do not develop obvious systemic external progeroid features and have near‑normal lifespans. Nevertheless, they develop progressive vascular‑smooth‑muscle‑cell (VSMC) loss, fragmentation of internal elastic laminae, proteoglycan deposition and adventitial thickening within the aorta, carotid arteries and iliac arteries; vascular calcification emerges in aged individuals. This line precisely recapitulates the lethal vascular pathology observed in HGPS patient autopsy specimens. It is a frequently‑used model for evaluating anti‑vascular‑aging therapeutics and antisense oligonucleotide (ASO) interventions.

References

1. Eriksson M, Brown WT, Gordon LB, et al. Recurrent de novo point mutations in lamin A cause Hutchinson‑Gilford progeria syndrome. Cell. 2003;114(4):543‑554.
2. Varga R, Eriksson M, Erdos MR, et al. Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson‑Gilford progeria syndrome. PNAS. 2006;103(9):3250‑3255.
3. Zhang H, Kieckhaefer JE, Cao K. Mouse models of laminopathies. Aging Cell. 2013;12(1):2‑10.