Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria.

The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation.

Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice.

The nuclear lamina is an approximately 10 nm thick proteinaceous layer underlying the inner nuclear membrane. The A-type lamins, nuclear intermediate filament proteins encoded by the LMNA gene, are basic components of the nuclear lamina. Mutations in LMNA are associated with the laminopathies, congenital diseases affecting tissue regeneration and homeostasis.

Mutations in the mouse Lmna gene causing progeria, muscular dystrophy and cardiomyopathy.

At least ten different diseases have been linked to mutations in proteins associated with the nuclear envelope (NE). Eight of these diseases are associated with mutations in the lamin A gene (LMNA). These diseases include the premature ageing or progeric diseases Hutchinson-Gilford progeria and atypical Werner's syndrome, diseases affecting striated and cardiac muscle including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting white fat deposition and skeletal development and a peripheral neuropathy resulting in motor neuron demyelination.

A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation.

The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G(1) phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized.

Aging and nuclear organization: lamins and progeria.

The discoveries of at least eight human diseases arising from mutations in LMNA, which encodes the nuclear A-type lamins, have revealed the nuclear envelope as an organelle associated with a variety of fundamental cellular processes. The most recently discovered diseases associated with LMNA mutations are the premature aging disorders Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner's syndrome. The phenotypes of both HGPS patients and a mouse model of progeria suggest diverse compromised tissue functions leading to defects reminiscent of aging.

Functional identification of distinct sets of antitumor activities mediated by the FKBP gene family.

Assigning biologic function to the many sequenced but still uncharacterized genes remains the greatest obstacle confronting the human genome project. Differential gene expression profiling routinely detects uncharacterized genes aberrantly expressed in conditions such as cancer but cannot determine which genes are functionally involved in such complex phenotypes. Integrating gene expression profiling with specific modulation of gene expression in relevant disease models can identify complex biologic functions controlled by currently uncharacterized genes.

The laminopathies: nuclear structure meets disease.

Most inherited diseases are associated with mutations in a specific gene. Sometimes, mutations in two or more different genes result in diseases with a similar phenotype. Rarely do different mutations in the same gene result in a multitude of seemingly different and unrelated diseases.

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

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). HGPS is a rare genetic disorder resulting in phenotypes suggestive of accelerated ageing, including shortened stature, craniofacial disproportion, very thin skin, alopecia and osteoporosis, with death in the early teens predominantly due to atherosclerosis. However, recent reports suggest that developmental abnormalities may also be important in HGPS.