Progeria

What is progeria?
 * First reported case in 1886
 * Full name is Hutchinson-Gilford Progeria Syndrome
 * =====Premature aging syndrome=====
 * =====Patients typically appear normal a birth; onset of symptoms begins around 2 years old=====
 * =====Patients have a life expectancy range of 7-20 years old=====
 * =====Although they exhibit many signs of aging such as poor muscle development and bone density, patients “do not show any increase in tumor susceptibility, cataract formation or cognitive degeneration, features often associated with normal aging, and HGPS has therefore been referred to as a segmental progeroid syndrome, as it only partially reproduces the aging process” (Mounkes, et. al).=====
 * =====Caused by mutations in the LMNA gene, thus affecting the protein it codes for, Lamin A and the functionality of the nuclear lamina=====

What is the nuclear lamina?
 * The nucleus of a cell is enclosed in a plasma membrane lipid bilayer, with scattered nuclear pores to allow for passage of certain materials into an out of the nucleus. The nuclear lamina is a protein network scaffolding that envelops the inner nuclear membrane.
 * =====The nuclear lamina plays a role with the cell’s DNA.=====
 * “The nuclear lamina is a complex ensemble of proteins that connects the inner nuclear membrane to chromatin, and thus creates a link from the cytoplasm to the genome” (Bridger).
 * =====Additionally, the nuclear lamina gives support and shape to the nucleus.=====
 * “The nuclear lamina structurally supports the nuclear envelope (NE) and largely determines the overall shape of the interphase nucleus. In addition, the lamina associates with chromatin both directly and indirectly and has been implicated in the regulation of gene expression and in DNA synthesis” (Mounkes, et.al).

What is Lamin A?
 * LMNA gene codes for the protein Lamin A protein
 * =====Lamin A is an intermediate filament.=====
 * =====“The lamins are type V intermediate filament (IF) proteins comprising the major structural components of the nuclear lamina, the fibrous meshwork underlying the inner nuclear membrane” (Taimen, et. al)=====
 * =====There are two distinct types of nuclear lamins.=====
 * " Lamins are divided into A- and B-types on the basis of their protein structure and expression patterns. B-type lamins are encoded by distinct genes and are present in all metazoan cells, whereas A-type lamins are derived through alternative splicing of a single gene and are present only in differentiated cells of more complex organisms” (Mattout, et. al).
 * Since Lamin A is formed from splicing genes, mutations in found in HGPS are caused by incorrect splicing.
 * "Although other //LMNA//mutations have been associated with HGPS, the most frequently occurring mutation is a single nucleotide change that results in activation of a cryptic splice site inside exon 11 and the subsequent loss of 50 amino acids within the carboxyl terminus of the encoded protein” (Kudlow, et. al)
 * Due to the loss of 50 amino acids, the remaining steps of the protein synthesis are then incorrect. Figure 2 below shows this differences in the normal synthesis versus synthesis in a HGPS patient.
 * Additionally, in patients with progeria, Δ50 lamin A accumulates in the nucleus.
 * "During normal aging, lamin A protein redistributes away from the sites in the nuclear interior. This is associated with a decline in the nuclear morphology and increased evidence of DNA damage. In HGPS cells, the process is highly accelerated, probably because Δ50 lamin A levels accumulate to much higher levels than in normal cells. Treating either aged fibroblasts or HGPS fibroblasts with a morpholino targeted to Δ50 lamin A reverses some of these defects" (Kudlow, et al.).

REFERENCES Kudlow, Brian A., Brian K. Kennedy. (2006) Aging: Progeria and the Lamin Connection. //Current Biology//. **16.16**. 652-654.

Taimen, Pekka, Katrin Pflegharr, Takeshi Shimi, Dorothee Moller, Kfir Ben-Harush, Michael R. Erdos, Stephen A. Adam, Harald Herrmann, Ohad Medalia, Francis S. Collins, Anne E. Goldman, Robert D. Goldman. (2009) A Progeria Mutation Reveals Functions for Lamin A in Nuclear Assembly, Architecture, and Chromosome Organization. //Proceedings of the National Academy of Sciences of the United States of America//. **106.49**. 20788-20793

Mounkes, Leslie C., Colin L. Stewart. (2004) Aging and Nuclear Organization: Lamins and Progeria. //Current Opinion in Cell Biology//. **16.3**. 322-327

Bridger, Joanna M., Nicole Foeger, Ian R. Kill, Harald Herrmann. (2007) The Nuclear Lamina. //FEBS Journal//. **274.6**. 1354-1361.

Mattout, Anna., Thomas Dechat, Stephen A Adam, Robert D Goldman, Yosef Gruenbaum. (2006) Nuclear Lamins, Diseases, and Aging. //Current Opinion in Cell Biology//. **18.3**. 335-341.