Hutchinson-Gilford progeria syndrome is a genetic condition characterized by the dramatic, rapid appearance of aging beginning in childhood. Affected children typically look normal at birth and in early infancy, but then grow more slowly than other children and do not gain weight at the expected rate (failure to thrive). They develop a characteristic facial appearance including prominent eyes, a thin nose with a beaked tip, thin lips, a small chin, and protruding ears. Hutchinson-Gilford progeria syndrome also causes hair loss (alopecia), aged-looking skin, joint abnormalities, and a loss of fat under the skin (subcutaneous fat). This condition does not affect intellectual development or the development of motor skills such as sitting, standing, and walking.

People with Hutchinson-Gilford progeria syndrome experience severe hardening of the arteries (arteriosclerosis) beginning in childhood. This condition greatly increases the chances of having a heart attack or stroke at a young age. These serious complications can worsen over time and are life-threatening for affected individuals.

Progeria is an extremely rare genetic disease of childhood characterized by dramatic, premature aging.

What do we know about heredity and progeria?

Progeria is an extremely rare genetic disease of childhood characterized by dramatic, premature aging. The condition, which derives its name from "geras," the Greek word for old age, is estimated to affect one in 4 million newborns worldwide.

The most severe form of the disease is Hutchinson-Gilford progeria syndrome, recognizing the efforts of Dr. Jonathan Hutchinson, who first described the disease in 1886, and Dr. Hastings Gilford who did the same in 1904.

As newborns, children with progeria usually appear normal. However, within a year, their growth rate slows and they soon are much shorter and weigh much less than others their age. While possessing normal intelligence, affected children develop a distinctive appearance characterized by baldness, aged-looking skin, a pinched nose, and a small face and jaw relative to head size. They also often suffer from symptoms typically seen in much older people: stiffness of joints, hip dislocations and severe, progressive cardiovascular disease. However, various other features associated with the normal aging process, such as cataracts and osteoarthritis, are not seen in children with progeria.

Some children with progeria have undergone coronary artery bypass surgery and/or angioplasty in attempts to ease the life-threatening cardiovascular complications caused by progressive atherosclerosis. However, there currently is no treatment or cure for the underlying condition. Death occurs on average at age 13, usually from heart attack or stroke.

In 2003, NHGRI researchers, together with colleagues at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, discovered that Hutchinson-Gilford progeria is caused by a tiny, point mutation in a single gene, known as lamin A (LMNA). Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears in nearly all instances to occur in the sperm prior to conception. It is remarkable that nearly all cases are found to arise from the substitution of just one base pair among the approximately 25,000 DNA base pairs that make up the LMNA gene.

The LMNA gene codes for two proteins, lamin A and lamin C, that are known to play a key role in stabilizing the inner membrane of the cell's nucleus. In laboratory tests involving cells taken from progeria patients, researchers have found that the mutation responsible for Hutchinson-Gilford progeria causes the LMNAgene to produce an abnormal form of the lamin A protein. That abnormal protein appears to destabilize the cell's nuclear membrane in a way that may be particularly harmful to tissues routinely subjected to intense physical force, such as the cardiovascular and musculoskeletal systems.

Interestingly, different mutations in the same LMNA gene have been shown to be responsible for at least a half-dozen other genetic disorders, including two rare forms of muscular dystrophy.

In addition to its implications for diagnosis and possible treatment of progeria, the discovery of the underlying genetics of this model of premature aging may help to shed new light on humans' normal aging process.

Is there a test for progeria?

A genetic test for Hutchinson-Gilford progeria syndrome, also called HGPS, is currently available. In the past, doctors had to base a diagnosis of progeria solely on physical symptoms, such as skin changes and a failure to gain weight, that were not fully apparent until a child's first or second year of life. This genetic test now enables doctors to diagnose a child at a younger age and initiate treatment early in the disease process.

This genetic test for Hutchinson-Gilford progeria syndrome also serves to reassure parents of affected children that their disorder stems from a sporadic genetic mutation and that therefore it is unlikely that any future offspring would have the condition.

This condition is very rare; it is reported to occur in 1 in 4 million newborns worldwide. More than 130 cases have been reported in the scientific literature since the condition was first described in 1886.

Mutations in the LMNA gene cause Hutchinson-Gilford progeria syndrome. The LMNA gene provides instructions for making a protein called lamin A. This protein plays an important role in determining the shape of the nucleus within cells. It is an essential scaffolding (supporting) component of the nuclear envelope, which is the membrane that surrounds the nucleus. Mutations that cause Hutchinson-Gilford progeria syndrome result in the production of an abnormal version of the lamin A protein. The altered protein makes the nuclear envelope unstable and progressively damages the nucleus, making cells more likely to die prematurely. Researchers are working to determine how these changes lead to the characteristic features of Hutchinson-Gilford progeria syndrome.

Normal Function

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 are made up of 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 supporting (scaffolding) 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 and other proteins 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. Lamins A and C are also found inside the nucleus, and researchers believe the proteins may play a role in regulating the activity (expression) 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.

Health Conditions Related to Genetic Changes

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Emery-Dreifuss muscular dystrophy

More than 130 mutations in the LMNA gene have been identified in people with Emery-Dreifuss muscular dystrophy, a condition that affects muscles used for movement (skeletal muscles) and the heart (cardiac muscle). This condition is characterized by joint deformities called contractures, which restrict the movement of certain joints; muscle weakness and wasting that worsen over time; and heart problems, including an increased risk of sudden death.

Most of the LMNA gene mutations that cause Emery-Dreifuss muscular dystrophy change single protein building blocks (amino acids) in lamins A and C, which alters the structure of these proteins. The effect of LMNA gene mutations 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 continue to investigate how LMNA mutations affect skeletal muscles and cardiac muscle, leading to the characteristic features of Emery-Dreifuss muscular dystrophy.

Familial partial lipodystrophy

Several mutations in the LMNA gene have been found to cause familial partial lipodystrophy type 2 (also known as familial partial lipodystrophy, Dunnigan type), a rare condition characterized by an abnormal distribution of fatty (adipose) tissue in the body. Adipose tissue is lost from the arms, legs, and hips, and excess fat is deposited in the face, neck, and 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. The effects of LMNA gene mutations on adipocytes are not well understood. Studies suggest that these mutations may weaken the nuclear envelope, ultimately leading to the premature death of these cells 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 mutation in the LMNA gene has been found in most patients with Hutchinson-Gilford progeria syndrome, which is a condition that causes the dramatic, rapid appearance of aging beginning in childhood. 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. Although the C1824T mutation is not predicted to change an amino acid, it alters the way the gene's instructions are used to make a protein. 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 prelamin A that cannot be processed correctly within the cell. When the altered protein is incorporated into the 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

At least 15 mutations in the LMNA gene have been reported to cause LMNA-related congenital muscular dystrophy (L-CMD), a rare condition characterized by skeletal muscle weakness and atrophy beginning very early in life. Most of the mutations 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.

The mutations that cause L-CMD lead to the production of abnormal lamins. These malfunctioning proteins 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 muscle weakness and atrophy in people with L-CMD.

Some of the mutations 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 (described above). It is unclear why certain mutations can cause different disorders in different people.

Mandibuloacral dysplasia

At least four mutations in the LMNA gene 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 affecting the limbs (type A lipodystrophy). The LMNA gene mutations that cause this condition change single amino acids in the lamin A and lamin C proteins. The most common mutation replaces the amino acid arginine at position 527 with the amino acid histidine (written as Arg527His or R527H).

The effects of LMNA gene mutations in this condition are not well understood. The amino acid changes may affect the structure of the lamin A or lamin C protein, or both, and alter how they interact 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 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

Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial atrial fibrillation

Familial dilated cardiomyopathy

MedlinePlus Genetics provides information about Familial dilated cardiomyopathy

Left ventricular noncompaction

MedlinePlus Genetics provides information about Left ventricular noncompaction

Limb-girdle muscular dystrophy

MedlinePlus Genetics provides information about Limb-girdle muscular dystrophy

Other disorders

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

In addition to the health conditions listed above, mutations 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 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 similar abnormalities in bone development and fat distribution as mandibuloacral dysplasia, although they are typically milder in APS.

Mutations in the LMNA gene have also been identified in newborns with a disorder called lethal restrictive dermopathy. Infants with this disorder have tight, rigid skin; underdeveloped lungs; and other abnormalities. They do not usually survive past the first week of life.

Researchers have not determined how mutations in the LMNA gene result in 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.

Other Names for This Gene

• LMN1
• LMNA_HUMAN

Genomic Location

Hutchinson-Gilford progeria syndrome is considered an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. The condition results from new mutations in the LMNA gene, and almost always occurs in people with no history of the disorder in their family.

• Poor growth (failure to thrive)
• Large head size relative to face
• Loss of fat under the skin
• Delayed eruption of teeth and other dental abnormalities
• Baldness (alopecia)
• Stiff joints
• Thin, weak bones (osteoporosis)
• Progressive heart disease
• Normal intelligence

• Neurologist
• Dermatologist
• Dentist
• Orthopedist
• Cardiologist
• Nutritionist
• Otolaryngologist
• Medical geneticist