An individual carrying a mutation in a single gene, do not show any symptom and hence Progeria is called an autosomal recessive disease. Researchers from NHGRI and the colleagues from the Progeria Research foundation, University of Michigan, the New York Institute for Basic Research in Developmental Disabilities, together found that Progeria, is caused a tiny, point mutation in a single gene, known as lamin A referred to as LMNA
Point mutation in the LMNA gene that encodes the protein Lamina A which is a part of the building blocks of nuclear envelope. Hence, the production of abnormal Lamina A proteins leads to premature death of cells. It is not inherited but it is almost always a chance occurrence that is extremely rare. Progeria is related with these diseases Scleroderma, Xeroderma pigmentosum, Werner’s syndrome and Cockayne’s syndrome.
Progeria is disorder that happens in childhood, because of a point mutation in position 1824 of the LMNA gene, replacing Cytosine with Thymine resulting in the creation of a unstable form of protein called Lamin A, which is a part of the building blocks of the nuclear envelope.
Progeria is not caused by defective DNA repair, like the accelerated aging diseases, which by themselves are erroneously labelled. They are called as Segmental Progerias because these diseases display what are considered different aspects of aging, but never every aspect.
Genetic cause of progeria:
LMNA is the structural scaffolding that holds the nucleus of a cell together. This gene provides instructions for making several slightly different proteins called lamins. The two major proteins produced from this gene, lamin A and lamin C, are made in most of the body's cells. These proteins have a nearly identical sequence of protein building blocks (amino acids). The small difference in the sequence makes lamin A longer than lamin C.
Lamins A and C are structural proteins called intermediate filament proteins. Intermediate filaments provide stability and strength to cells. Lamins A and C, located in the nuclear lamina, are essential scaffolding (supporting) components of the nuclear envelope, which is a structure that surrounds the nucleus in cells. The nuclear envelope regulates the movement of molecules into and out of the nucleus, and researchers believe it may play a role in regulating the activity of certain genes.
The lamin A protein must be processed within the cell before becoming part of the lamina. Its initial form, called prelamin A, undergoes a complex series of steps that are necessary for the protein to be inserted into the lamina. Lamin C does not have to undergo this processing before becoming part of the lamina.
A specific mutation in the LMNA gene has been found in 90% of the patients with Hutchinson-Gilford progeria syndrome. This mutation changes a single DNA building block (nucleotide) in the gene. Specifically, the mutation replaces the nucleotide cytosine with the nucleotide thymine at position 1824 (written as C1824T). This mutation is also sometimes noted as Gly608Gly or G608G, which refers to the position in the lamin A protein affected by the mutation. The C1824T mutation leads to an abnormal version of the lamin A protein called progerin, which is missing 50 amino acids near one end. The location of this mutation does not affect the production of lamin C. Other mutations in the LMNA gene have been identified in a small number of people with the features of Hutchinson-Gilford progeria syndrome.
The mutations responsible for this disorder result in an abnormal form of lamin A that cannot be processed correctly within the cell. When the altered protein is integrated into the lamina, it can disrupt the shape of the nuclear envelope. Over time, a buildup of this altered protein appears to damage the structure and function of the nucleus, making cells more likely to die prematurely leading to the development of the condition called progeria.
