A progeroid syndrome in mice is caused by defects in A-type lamins

  title={A progeroid syndrome in mice is caused by defects in A-type lamins},
  author={Leslie C. Mounkes and Serguei Kozlov and Lidia Hernandez and Teresa Sullivan and Colin L Stewart},
Numerous studies of the underlying causes of ageing have been attempted by examining diseases associated with premature ageing, such as Werner's syndrome and Hutchinson–Gilford progeria syndrome (HGPS. [] Key Method Here we describe the derivation of mice carrying an autosomal recessive mutation in the lamin A gene (Lmna) encoding A-type lamins, major components of the nuclear lamina. Homozygous mice display defects consistent with HGPS, including a marked reduction in growth rate and death by 4 weeks of…

Targeted transgenic expression of the mutation causing Hutchinson-Gilford progeria syndrome leads to proliferative and degenerative epidermal disease

Tetracycline-inducible transgenic lines that carry a minigene of human LMNA under the control of a tet-operon are generated and these transgenic mice appear to be good models for studies of the molecular mechanisms of skin abnormalities in HGPS and other related disorders.

The genetic mechanism that links Hutchinson-Gilford progeria syndrome to physiological aging.

The research was primarily designed to study the expression of LMNA and the global genome differential splicing in aging cells to investigate the potential relationships that link the genetic mechanisms found in HGPS to those occurring in normal physiological aging.

Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome

It is reported that heterozygous, recurrent de novo point mutations in the lamin A/C gene, a component of the filamentous meshwork of the nuclear lamina, caused Hutchinson-Gilford progeria syndrome.


The clinical characteristics of this disease, the underlying mutation in the lamin A (LMNA) gene that results in this phenotype and the recent advances in treatment strategies are summarized.

Accelerated aging syndromes, are they relevant to normal human aging?

Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.

Embryonic Senescence and Laminopathies in a Progeroid Zebrafish Model

New zebrafish models for a human premature aging disorder are generated and the utility for studying laminopathies is demonstrated, which may provide a new platform for future drug screening as well as genetic analyses aimed at identifying modifier genes that influence not only progeria and laminationopathies but also other age-associated human diseases common in vertebrates.

Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson–Gilford progeria syndrome

A mouse model for progeria is created by generating transgenics carrying a human bacterial artificial chromosome that harbors the common HGPS mutation, and these mice develop progressive loss of vascular smooth muscle cells in the medial layer of large arteries, in a pattern very similar to that seen in children with HGPS.

Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome

It is shown that the cellular disease phenotype is reversible in cells from individuals with HGPS, and proof of principle for the correction of the premature aging phenotype is established.

Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies.

The results demonstrate that LmnaH 222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.



Hutchinson-Guilford progeria syndrome

HGPS is associated with several features of premature ageing—for example, growth retardation, characteristic facies, loss of hair, and subcutaneous fat, restricted joint mobility, prominent eyes, and severe premature atherosclerosis.

Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy.

Results suggest that nuclear structural defects could contribute to the etiology of both dilated cardiomyopathy and autosomal dominant Emery-Dreifuss muscular dystrophy.


The pathologic changes noted at autopsy on a 20-year-old woman with classic features of Hutchinson-Gilford progeria syndrome are reported, including an increased urinary excretion of hyaluronic acid.

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy

This work has mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus, and identified four mutations in LMNA that co-segregate with the disease phenotype in the five families.

Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene.

The mechanical properties of nuclear envelopes were altered, as judged from the extensive deformations observed in nuclei from heat-shocked cells, and from the low stringency of extraction of their components.

Loss of a-Type Lamin Expression Compromises Nuclear Envelope Integrity Leading to Muscular Dystrophy

It is shown that mice lacking A-type lamins develop to term with no overt abnormalities, however, their postnatal growth is severely retarded and is characterized by the appearance of muscular dystrophy.

The nuclear lamina and inherited disease.

Life at the edge: the nuclear envelope and human disease

Attempts to resolve this paradox are uncovering new molecular interactions — both inside the nucleus and at its periphery — which indicate that the nuclear envelope has functions that go beyond mere housekeeping.