What+is+the+LMNA+Gene?

What is the //LMNA// Gene?

The //LMNA// gene, otherwise known as "lamin A/C" gives instructions for making several slightly different proteins called lamins; lamin A and lamin C respectively (4). These structural proteins or "intermediate filament proteins" are located in the nuclear lamina which is attached to the inner membrane of the nuclear envelope (the structure that surrounds the nucleus in cells) where they act as essential supporting components (4). Lamins not only have a structural role in supporting the nuclear envelope but it has been implicated they serve a purpose in many other nuclear functions as well. For example, mitosis, DNA synthesis and repair, RNA transcription and processing, apoptosis, organization of chromatin structure and regulation of gene expression (6).



While lamin C does not have to undergo any processing before becoming part of the lamina (mesh-like layer of intermediate filaments), lamin A does. In order to do so it must start in it's initial form, prelamin A, and undergo a fairly complex series of steps before it can become a mature lamin A and be inserted into the lamina (4).

 In a normal cells process, the W//ild Type// (WT) prelamin A (wild type being the typical form of the //LMNA// gene as it occurs in nature) contains a CaaX tetrapeptide motif at the C terminus. This tetrapeptide signals the addition of a 15-carbon farnesyl isoprenoid lipid called a farnesyl group to the cysteine using the farnesyltransferase (FTase) enzyme (5). The farnesyl group promotes prelamin A to associate with the nuclear membrane of the cell.

Once farnesylation is complete the terminal AAX amino acids are removed causing the C terminal cystein to undergo methylation (5). Unique to lamin A, there is a second cleavage site within the nucleus that causes the removal of an additional 15 C-terminal amino acids from the mature protein, including the farnesylated cysteine (5).

The last cleavage step which causes the loss of the farnesyl group anchoring the prelamin A to the nuclear membrane releases prelamin A from the mature protein and allows it to be inserted into the nuclear lamina as a mature lamin A (5).

In addition to the knowing the normal process of converting prelamin A to lamin A, the //LMNA// gene location on the chromosome is also important in understanding how the mutation of the gene that causes HGPS works.

It's cytogenetic location is 1q22 and it's molecular location on chromosome 1 is base pairs 156,084,460 to 156, 109, 877 (4). The cytogenetic shorthand location (1q22) merely indicates the //LMNA// gene is located on the long (q) arm of chromosome 1 at position 22 and molecularly, the //LMNA// gene is located from base pair 156, 084, 460 to 156, 109, 877 on chromosome 1 (4).



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(4) Genetics Home Reference (2011). //LMNA.// Retrieved from http://ghr.nlm.nih.gov/gene/LMNA (5) Capell, B., Collins, F., Conneely, K., Cox, A., Der, C., Erdos, M., Fiordalisi, J.,Gordon, L., Madigan, J., Varga, R. (2005). //Inhibiting Farnesylation of Progerin Prevents the Characteristic Nuclear Blebbing of Hutchinson-Gilford Progeria Syndrome.// Retrieved from http://www.pnas.org/content/102/36/12879.full (6) Aaronson, S., Benson, E., Lee, S. (2010). //Role of Progerin-Induced Telomere Dysfunction in HGPS Premature cellular senescence.//Retrieved from []