LMNA

The LMNA 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 are essential scaffolding (supporting) components of the nuclear envelope, which is a structure that surrounds the nucleus in cells. Specifically, these proteins are located in the nuclear lamina, a mesh-like layer of intermediate filaments that is attached to the inner membrane of the nuclear envelope. 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.

Charcot-Marie-Tooth disease - caused by mutations in the LMNA gene

At least one LMNA mutation has been identified in people with a form of Charcot-Marie-Tooth disease known as type 2B1. The mutation changes a single amino acid in the LMNA proteins. Specifically, the amino acid arginine is replaced by the amino acid cysteine at protein position 298 (written as Arg298Cys or R298C). Although its effect is not fully understood, the Arg298Cys mutation alters a protein region important for interactions with other molecules. It is unclear how the altered LMNA proteins contribute to the signs and symptoms of type 2B1 Charcot-Marie-Tooth disease.

Emery-Dreifuss muscular dystrophy - caused by mutations in the LMNA gene

More than 100 mutations in the LMNA gene have been identified in people with Emery-Dreifuss muscular dystrophy. Most of these mutations change single amino acids in lamins A and C, which alters the structure of these proteins. The effect of LMNA mutations within cells remains unclear. Abnormal versions of lamins A and C may alter the activity of certain genes or weaken the structure of the nucleus, making cells more fragile. Researchers continue to investigate how LMNA mutations affect muscles used for movement (skeletal muscles) and heart (cardiac) muscle, leading to the characteristic features of Emery-Dreifuss muscular dystrophy.

Hutchinson-Gilford progeria syndrome - caused by mutations in the LMNA gene

A specific mutation in the LMNA gene has been found in most 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 version of lamin A that cannot be processed correctly within the cell. When the altered protein is incorporated 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. Researchers are working to determine how these changes lead to the signs and symptoms of Hutchinson-Gilford progeria syndrome.

other disorders - caused by mutations in the LMNA gene

Mutations in the LMNA gene have been found to cause several other inherited conditions. Because the conditions result from mutations in lamin proteins, they are known as laminopathies. A laminopathy called limb-girdle muscular dystrophy type 1B affects skeletal and cardiac muscle. Another condition, familial dilated cardiomyopathy with conduction defects, has severe effects on cardiac muscle that result in life-threatening heart problems. The features of these laminopathies overlap with those of the autosomal dominant form of Emery-Dreifuss muscular dystrophy. Because certain LMNA mutations may be responsible for any of these conditions, researchers suspect that limb-girdle muscular dystrophy type 1B and familial dilated cardiomyopathy with conduction defects may be variants of Emery-Dreifuss muscular dystrophy instead of separate disorders.

Other laminopathies affect the amount and distribution of fat in the body. Dunnigan type partial lipodystrophy is characterized by a loss of fatty tissue from the trunk and limbs, and a buildup of fat around the neck and shoulders. Mandibuloacral dysplasia also alters the distribution of fatty tissue and causes abnormalities in some bones, particularly in the jaw, hands, and feet.

Researchers have not determined how mutations in the LMNA gene result in this diverse group of disorders. They believe that altered lamin proteins could disrupt the activity of genes in specific tissues. Altered lamins may also weaken the structure of the nucleus in some cells, making them more fragile.