GRN-related frontotemporal lobar degeneration is a progressive brain disorder that can affect behavior, language, and movement. The symptoms of this disorder usually become noticeable in a person's fifties or sixties, and affected people typically survive 7 to 13 years after the appearance of symptoms. However, symptoms can begin as early as a person's thirties or as late as a person's eighties. The features of this condition vary significantly, even among affected members of the same family.

Behavioral changes are the most common early signs of GRN-related frontotemporal lobar degeneration. These include marked changes in personality, judgment, and insight. It may become difficult for affected individuals to interact with others in a socially appropriate manner. Affected people may also become easily distracted and unable to complete tasks. They increasingly require help with personal care and other activities of daily living.

Many people with GRN-related frontotemporal lobar degeneration develop progressive problems with speech and language (aphasia). Affected individuals may have trouble speaking, remembering words and names (dysnomia), and understanding speech. Over time, they may completely lose the ability to communicate (mutism). People with this condition also experience a decline in intellectual function (dementia).

Some people with GRN-related frontotemporal lobar degeneration also develop movement disorders, such as parkinsonism and corticobasal syndrome. The signs and symptoms of these disorders include tremors, muscle stiffness (rigidity), unusually slow movement (bradykinesia), walking problems (gait disturbance), involuntary muscle spasms (myoclonus), uncontrolled muscle tensing (dystonia), and an inability to carry out purposeful movements (apraxia).

GRN-related frontotemporal lobar degeneration results from mutations (pathogenic variants) in the GRN gene. This gene provides instructions for making a protein called progranulin. Progranulin is active in many different tissues in the body, where it helps control the growth, division, and survival of cells. Progranulin's function in the brain is not well understood, although it appears to play an important role in the survival of nerve cells (neurons).

Most mutations in the GRN gene prevent any progranulin from being produced from one copy of the gene in each cell. As a result, cells make only half the usual amount of progranulin. It is unclear how a shortage of this protein leads to the features of GRN-related frontotemporal lobar degeneration. However, studies have shown that the disorder is characterized by the buildup of a protein called TAR DNA-binding protein 43 (TDP-43) in certain brain cells. The TDP-43 protein forms clumps (aggregates) that may interfere with cell functions and ultimately lead to cell death. Researchers are working to determine how mutations in the GRN gene, and the resulting loss of progranulin, are related to a buildup of TDP-43 in the brain.

The features of GRN-related frontotemporal lobar degeneration result from the gradual loss of neurons in regions near the front of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. The death of neurons in these areas causes problems with many critical brain functions. However, it is unclear why the loss of neurons occurs in the frontal and temporal lobes more often than other brain regions in people with GRN-related frontotemporal lobar degeneration.

Normal Function

The GRN gene provides instructions for making a protein called progranulin. This protein is primarily found in the membrane of cellular structures called lysosomes, which are specialized compartments that digest and recycle materials. Within lysosomes, progranulin can be cut (cleaved) into smaller proteins, known as granulins, which are thought to function similar to progranulin.

Progranulin is found in tissues throughout the body, but it is most active in cells that are dividing rapidly, such as skin cells (fibroblasts), immune system cells, and certain brain cells. This protein helps regulate the growth, division, and survival of these cells. It also plays important roles in early embryonic development, wound healing, and the body's immune response to injury (inflammation). Progranulin is active in several types of brain cells. However, little is known about this protein's role in the brain. It appears to be critical for the survival of nerve cells (neurons).

Health Conditions Related to Genetic Changes

CLN11 disease

At least eight mutations in the GRN gene have been found to cause CLN11 disease. This condition is characterized by recurrent seizures (epilepsy), vision loss, problems with balance and coordination (cerebellar ataxia), and a decline in intellectual function that typically begin in adolescence or early adulthood.

Most of the GRN gene mutations that cause CLN11 disease disrupt how the gene's information is spliced together to make the blueprint for producing the progranulin protein. As a result, there is a complete loss of functional progranulin protein. This lack of progranulin leads to the death of nerve cells in the brain. Although the exact mechanism is unknown, it is thought to involve impaired function of lysosomes. Unlike in GRN-related frontotemporal lobar degeneration (described below), people with CLN11 disease do not appear to have build up of the TDP-43 protein in their brain cells. In CLN11 disease, loss of neurons from many regions of the brain leads to the development of epilepsy, cerebellar ataxia, and other signs and symptoms in adolescence or early adulthood.

GRN-related frontotemporal lobar degeneration

More than 65 mutations in the GRN gene have been identified in people with GRN-related frontotemporal lobar degeneration. This condition is a progressive brain disorder that can affect behavior, language, and movement. The symptoms of this disorder usually become noticeable in a person's fifties or sixties.

The most common GRN gene mutation, which is written as Arg493Ter or R493*, creates a premature stop signal in the instructions for making progranulin. Most of the mutations that cause GRN-related frontotemporal lobar degeneration prevent any protein from being produced from one copy of the GRN gene in each cell. As a result of these genetic changes, cells make only half the usual amount of progranulin. In rare cases, affected individuals have mutations in both copies of their GRN gene. Each of these mutations allow for some functional protein to be produced and when measured, the total amount of progranulin produced amounts to about half of the usual amount.

It is unclear how a shortage of progranulin leads to the features of GRN-related frontotemporal lobar degeneration. However, studies have shown that the disorder is characterized by the buildup of a protein called TAR DNA-binding protein 43 (TDP-43) in certain brain cells. The TDP-43 protein forms clumps (aggregates) that may interfere with cell functions and ultimately lead to cell death. Researchers are working to determine how mutations in the GRN gene, and the resulting loss of progranulin, are related to a buildup of TDP-43 in the brain.

The features of GRN-related frontotemporal lobar degeneration result from the gradual loss of neurons in regions near the front of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. The death of neurons in these areas causes problems with many critical brain functions. However, it is unclear why the loss of neurons occurs in the frontal and temporal lobes more often than other brain regions in people with GRN-related frontotemporal lobar degeneration.

Other Names for This Gene

• acrogranin
• CLN11
• GEP
• GP88
• granulin
• granulin-epithelin
• granulins
• granulins precursor
• GRN_HUMAN
• PC cell-derived growth factor
• PCDGF
• PEPI
• PGRN
• proepithelin
• progranulin

Genomic Location

GRN-related frontotemporal lobar degeneration has a pattern of inheritance known as incomplete autosomal dominance. This means having one copy of the altered gene generally results in milder signs and symptoms than having both copies of the altered gene. People with a mutation in one copy of the GRN gene in each cell (heterozygotes) have some functional progranulin protein and develop GRN-related frontotemporal lobar degeneration. Usually, people with a mutation in both copies of the GRN gene in each cell (homozygotes) do not produce any functional progranulin protein. These individuals have the signs and symptoms of another condition called CLN11 disease, in which movement and neurological problems begin in adolescence or early adulthood. However, some people with two GRN gene mutations that allow the production of some functional progranulin protein have GRN-related frontotemporal lobar degeneration.

In most cases of GRN-related frontotemporal lobar degeneration, an affected person has a parent and other family members with the condition.

The prevalence of GRN-related frontotemporal lobar degeneration varies worldwide. It affects an estimated 3 to 15 per 100,000 people aged 45 to 64.