LMNA+Mutations

//LMNA// Mutations

In most patients with HGPS it has been found that a specific mutation in the //LMNA// gene is the culprit for the disorder. This mutation changes just one single DNA nucleotide (building block) in the gene replacing the nucleotide cytosine with the nucleotide thymine at position 1824 (written as C1824T) creating a cryptic splice donor site (4). This is enough to alter the normal cell process of lamin A completely disrupting the nuclear membrane and creating the abnormal morphology characteristic of the genetic disorders cells. The cryptic splice donor sit (C1824T) activation results in mRNA lacking 150 nucleotides which in turn, causes a 50 amino acid deletion at the C-terminus end (6). The exposure of the crypitc splice site in exon 11 due to the mutation results in an abnormal version of lamin A to be produced (6).

In order for normal lamin A processing to occur, the 50 amino acids which are deleted in the mutant version are required (5). Since those amino acids are no long present, lamin A remains permanently farnesylated. This results in the production of a mutant protein called "progerin" to be produced as well as the second cleavage site unique to lamin A to be skipped, resulting in prelamin A remaining anchored to the nuclear rim. Prelamin A now begins to accumulate in toxic amounts in the nuclear membrane causing it to look like the cell nucleus in the image above (right photo) (6).

Below is a more simplistic explanation of the steps in a normal cell (with wild type prelamin A) compared to those in a progeria cell (with mutant prelamin A) followed by another more complex explanation of the "normal prelamin A processing" discussed previously but now contrasted against HGPS.



In summary, lamin A has a second cleavage site which releases the farnesyl group from the prelamin A detaching it from the nuclear membrane and inserting it into the nuclear lamina (5). In HGPS, the 50 amino acid deletion (aa 606-656) removes the endoprotease recognition site which is necessary for executing the final cleavage site (5). This prevents a mature lamin A from being produced and instead creates a mutant farnesylated prelamin A termed progerin. When progerin is incorporated into the lamina, it disrupts the shape of the nuclear envelope and over time, the buildup of progerin can damage the structure and function of the nucleus causing premature cell death to occur (4). In large numbers, this begins to dramatically affect the body creating the symptoms of HGPS.

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(4) Genetics Home Reference (2011). //LMNA.// Retrieved from [] (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[] (6) Aaronson, S., Benson, E., Lee, S. (2010). //Role of Progerin-Induced Telomere Dysfunction in HGPS Premature cellular senescence.// Retrieved from http://jcs.biologists.org/content/123/15/2605.full (7) Buendia, B., Coppey-Moisan, M., Courvalin, J., Delbarre, E., Gaillard, C., Tramier, M. (2006). //The Truncated Prelamin A in Hutchinson-Gilford Progeria Syndrome Alters Segration of A-type and B-type Lamin Homopolymers.// Retrieved from http://hmg.oxfordjournals.org/content/15/7/1113.full