Medical science shows an increasing interest in Progeria. By researching what causes Progeria, scientists also hope to find a remedy for the normal aging process in humans. The search for the genetic defect that caused the accelerated aging effect, however, was like the search for a needle in a haystack. The human genome (the complete map of all genes in human DNA) contains approximately three billion base pairs that could be involved in the cause of a disease.

The French Dr. Nicolas Lévy discovered in a Progeria patient the location of the gene defect on the DNA. This discovery, done in 2003, was independently confirmed by American scientists.

Progeria is caused by a genetic defect in chromosome 1. Chromosome number 1 is the longest of human chromosomes. Chromosome 1 has nearly twice the number of genes of an average chromosome, making up nearly 8% of the human genome (3,141 different genes), and is also assumed to be involved in causing diseases such as Cancer, Parkinson’s disease, and Alzheimer.  

The LMNA gene

One of the 3,141 genes is the LMNA gene. A spontaneous mutation during one of the first cell divisions, shortly after conception, causes a defect in the LMNA-gene. Because this mutated gene continues to replicate, all the following copies contain the same defect. In every cell, there are two LMNA-genes (one from the mother and one from the father). Only one of these two contains the defect, but that gene is the dominant gene. With Progeria, the defect is found in the nucleus of each replicating cell. Non-replicating cells, such as found in the brain, function normally.

The LMNA gene does not cause the disease on its own. The gene provides the code with which the protein Lamin A and the protein Lamin C can be created. The defect in the genetic code causes protein Lamin A to be structured incorrectly, and as a result the protein does not function as it should. This incorrectly structured Progeria protein is called ‘Progerin’.

In Figure 1 below, it can be seen that the LMNA gene is found at the location 1q21.2. Its location is marked by the yellow arrow. Each chromosome has a p and a q arm. P (Petit = small) is the short arm, and q (the next letter in the alphabet) is the long arm. The arms are separated by a section that is called the centromere.

figure 1 [1] 

Functions of Lamin A

Lamin A is necessary to build the nuclear lamina layer in the cell nucleus.
On chromosome 1, the gene located at 1q21.2 contains the code for creating Lamin A and Lamin C. Lamin A creates a strong layer on the inside of the cell nucleus membrane (nuclear envelope). This layer is called the nuclear lamina. The nuclear lamina is created in two steps in a process known as farnesylation.


Step 1: The protein Lamin A attaches itself to amino acids [2], and forms a so-called Farnesyl group. These substances can bind because they contain compatible codes. The new substance that is formed in this way is a fibrous protein structure that attaches itself to the inside of the cell nucleus wall.

Step 2
: Subsequently Lamin A must still remove 15 amino acids, that is still attached, resembling a little tail of fat. When this tail of fat is ‘cut off’, it is possible for Lamin A  to form the strong lamina layer on the cell nucleus membrane.

The lamina layer in the cell nucleus is formed by a network of proteins. The lamina layer creates an envelope, and separates the cell nucleus from the cytoplasm. It is suspected that the lamina layer is also involved in communicating between the cell nucleus and the cytoplasm outside.

Lamin-A with Progeria
In Progeria patients, the second step in the farnesylation process is not completed properly. As a result, the Lamin A that has not been undone of the small ‘fat tails’, sticks to the inside of the cell membrane as a blubbery substance. (see figure 2)

The mutated Lamin A does not form a proper texture. The protein cannot recognise the enzymes, which normally break down the amino acids that make up the small ‘fat tails’. This results in a weak lamina layer. 
The resulting structurally incomplete lamina layer is called progerin.

The presence of fat disrupts all sorts of processes inside the cell. The ‘gates’ through which information is transported from the chromosomes in the cell nucleus to the cytoplasm outside are blocked. This prevents information from the cell nucleus to be sent into the body. The problems that Progeria patients experience, are most likely due to the undeveloped Lamin A.

The wall of the cell nucleus has many proteins that are stuck to it, and sometimes stuck halfway through: a part on the outside and a part on the inside. On the outside these proteins receive a stimulus or a signal, electric or from a chemical substance, and pass that on to the inside, with the message that for example, more, or maybe less, effort is required. In this fashion all sorts of stimuli from the outside reach the inside of the cell nucleus. There are thousands of these proteins. If such proteins do not function correctly, this causes deviations or diseases. Improperly structured Lamin A can cause proteins that are supposed to receive and transmit certain stimuli to malfunction. The presence of the fat still attached to Lamin A disrupts processes of information transmission in the cell. In this way, Lamin A influences the workings of thousands of other substances. 
And as a result, the mutated Lamin A, or progerin, can cause Progeria.

figure 2

Shown below are normal cells (left), at the right several cells that are affected. The difference is clearly visible. A healthy cell has a regular outline, where the Progeria cell has an unsteady shape. This difference is caused by the lamina layer, that lacks strength in a Progeria patient due to its incomplete structure.

figure 3

A beautiful illustrated explanation of the cause of progeria by Dr. Gordon can be seen at Fine Films on Vimeo.

[2] Amino acids are the elements/constituents of proteins. A protein can be made up of thousands of amino acids.