LMNA gene

Emery-Dreifuss muscular dystrophy

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the LMNA gene cause Emery-Dreifuss muscular dystrophy, a condition that affects the muscles used for movement (skeletal muscles) and the heart (cardiac) muscle. This condition is characterized by muscle weakness and wasting that worsens over time; joint deformities called contractures, which restrict the movement of certain joints; and heart problems, including an increased risk of sudden death. 

Most of the pathogenic variants in the LMNA gene that cause Emery-Dreifuss muscular dystrophy change single amino acids in lamins A and C, altering the structure of these proteins. The effect of these variants within cells is 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 are working to learn exactly how pathogenic variants in the LMNA gene affect skeletal muscles and cardiac muscle, leading to the characteristic features of Emery-Dreifuss muscular dystrophy. 

Familial partial lipodystrophy

Pathogenic variants in one copy of the LMNA gene in each cell can cause familial partial lipodystrophy type 2 (also known as familial partial lipodystrophy, Dunnigan type), a rare condition that is characterized by a loss of fatty (adipose) tissue in the body. In people with familial partial lipodystrophy type 2, adipose tissue that is located underneath the skin is lost from certain areas of the body, including the arms and legs, and excess fat is deposited in the face, neck, and inside the abdomen. The abnormal fat storage is related to changes in the development and function of adipocytes, which are the fat-storing cells in adipose tissue.

A common pathogenic variant that causes familial partial lipodystrophy type 2 changes a single amino acid in the lamin A and lamin C proteins. Specifically, it replaces the amino acid arginine at position 482 with the amino acids tryptophan (written as Arg482Trp) or glutamine (written as Arg482Gln). Studies suggest that this variant may weaken the nuclear envelope, ultimately leading to the premature death of adipocytes and leaving the body unable to store and use fats properly. These abnormalities of adipose tissue alter hormone production and affect many of the body's organs. However, it is unclear why the changes cause fat to be lost in some parts of the body and stored abnormally in others.

Hutchinson-Gilford progeria syndrome

A specific pathogenic variant in one copy of the LMNA gene in each cell has been found in many people with Hutchinson-Gilford progeria syndrome, which is a condition that causes the dramatic, rapid appearance of aging that begins in childhood. This pathogenic variant changes a single DNA building block (nucleotide) in the gene. Specifically, the variant replaces the nucleotide cytosine with the nucleotide thymine at position 1824 (written as C1824T) in the LMNA gene. Although the C1824T variant is not predicted to change an amino acid in lamin A, it alters the way the gene's instructions are used to make proteins. The C1824T variant causes cells to produce an abnormal version of the lamin A protein that is missing 50 amino acids near one end. The production of lamin C does not appear to be affected by this variant. 

The pathogenic variants that cause this disorder result in an abnormal version of lamin A. When the altered protein is incorporated into the nuclear lamina, it disrupts 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.

LMNA-related congenital muscular dystrophy

Pathogenic variants in the LMNA gene may also cause LMNA-related congenital muscular dystrophy (L-CMD), a rare condition that is characterized by skeletal muscle weakness and atrophy that begins very early in life. Most of the pathogenic variants that are associated with this disorder change single amino acids in lamin A and lamin C, while a few add or remove a small number of amino acids from these proteins.

These abnormal lamins alter the structure of the nuclear envelope in ways that are not well understood. Researchers are working to determine how these changes affect muscle cells and lead to the muscle weakness and atrophy seen in people with L-CMD.

Some of the pathogenic variants that have been identified in people with L-CMD seem to be unique to this disorder, while others have also been reported in people with other LMNA-related conditions, such as Emery-Dreifuss muscular dystrophy. It is unclear why certain pathogenic variants cause different disorders in different people.

Mandibuloacral dysplasia

Pathogenic variants in both copies of the LMNA gene in each cell can cause mandibuloacral dysplasia type A (MADA). This condition is characterized by a variety of signs and symptoms, which can include bone abnormalities; mottled or patchy skin coloring; and loss of fatty tissue under the skin, particularly in the arms and legs. The pathogenic variants in the LMNA gene that cause this condition change single amino acids in the lamin A and lamin C proteins.

The effects of the pathogenic variants that cause MADA are not well understood. The amino acid changes may alter the structure of the lamin A or lamin C proteins, which may affect their interactions with other proteins in the nuclear lamina. Some researchers speculate that these changes disrupt the nuclear envelope, making cells more fragile; however, it is unclear exactly how the altered lamin proteins contribute to the signs and symptoms of MADA.

Arrhythmogenic right ventricular cardiomyopathy

MedlinePlus Genetics provides information about Arrhythmogenic right ventricular cardiomyopathy

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial atrial fibrillation

Nonsyndromic dilated cardiomyopathy

MedlinePlus Genetics provides information about Nonsyndromic dilated cardiomyopathy

Other disorders

Pathogenic variants in the LMNA gene have been found to cause several other conditions. Health conditions that result from pathogenic variants in the LMNA gene are known as laminopathies. These disorders often have overlapping signs and symptoms, and the same pathogenic variant in the LMNA gene can cause different conditions. Researchers suspect that some laminopathies represent different forms of a single condition instead of separate disorders.

In addition to the health conditions listed above, pathogenic variants in the LMNA gene cause atypical progeroid syndrome (APS). The features of this condition are similar to those of Hutchinson-Gilford progeria syndrome and mandibuloacral dysplasia. As in people with Hutchinson-Gilford progeria syndrome, children with APS look as though they are aging prematurely, although the signs and symptoms of APS usually begin slightly later. APS can also cause abnormalities in bone development and fat distribution that are similar to those seen in people with mandibuloacral dysplasia, although these features are typically milder in people with APS.

Pathogenic variants in the LMNA gene can cause a condition called heart-hand syndrome, Slovenian type. This condition is characterized by heart problems and skeletal abnormalities of the fingers and toes. The feet are usually more severely affected than the hands. Heart problems include a form of heart disease in which the cardiac muscle becomes thin and enlarged (dilated cardiomyopathy) and abnormalities in the electrical system that coordinates the contractions of the heart chambers (cardiac conduction disease). This can lead to a disruption in the heart’s normal rhythm (arrhythmia). Affected individuals have an increased risk of sudden death.

Malouf syndrome is also caused by pathogenic variants in the LMNA gene. This condition is characterized by dilated cardiomyopathy and a condition called hypogonadotropic hypogonadism, which is caused by a reduction in the amount of hormones that direct sexual development.

Pathogenic variants in the LMNA gene have also been identified in newborns with a disorder called lethal restrictive dermopathy. Affected infants have multiple abnormalities, including tight, rigid skin and underdeveloped lungs. They typically do not survive past the first week of life.

Researchers have not determined how pathogenic variants in the LMNA gene cause this diverse group of disorders, but the multiple roles of the nuclear lamina in cells may help explain the wide variety of signs and symptoms.