DCTN1

The DCTN1 gene provides instructions for making a protein called dynactin-1. At least two different versions of this protein are produced in cells. The two versions differ in size; the larger version is called p150-glued, and the smaller version is called p135.

Dynactin-1 interacts with several other proteins to form a complex (a group of proteins that work together) called dynactin. The p150-glued version of dynactin-1 is the largest component (subunit) of the dynactin complex. This complex plays a critical role in cell division and the transport of materials within cells. To carry out these roles, the p150-glued subunit attaches (binds) to a protein called dynein, which acts as a motor, and to a track-like system of small tubes called microtubules. The dynactin complex, dynein, and microtubules work together like a conveyer belt to move materials within cells.

Researchers believe that the dynactin complex is particularly important for the proper function of axons, which are specialized extensions of nerve cells (neurons). Axons transmit impulses from nerve to nerve and from nerves to muscles. Axons can be quite long; some are more than 3 feet in length. The dynactin complex is a critical part of a rapid transport system that supplies axons with materials to keep them healthy and functioning efficiently.

Perry syndrome - caused by mutations in the DCTN1 gene

At least five mutations in the DCTN1 gene have been found to cause Perry syndrome. This progressive brain disease is characterized by a pattern of movement abnormalities known as parkinsonism, psychiatric changes, weight loss, and abnormally slow breathing (hypoventilation).

Most of the mutations that cause Perry syndrome change single protein building blocks (amino acids) in the dynactin-1 protein. These genetic changes impair the ability of the p150-glued version of dynactin-1 to bind to microtubules and transport materials within cells. Slow or abnormal transport of materials needed for the normal function of neurons causes these cells to malfunction and ultimately die. A gradual loss of neurons in areas of the brain that regulate movement, emotion, and breathing underlies the signs and symptoms of Perry syndrome.

amyotrophic lateral sclerosis - increased risk from variations of the DCTN1 gene

Researchers have identified a few mutations in the DCTN1 gene that may increase the risk of developing amyotrophic lateral sclerosis. These mutations change single amino acids in the dynactin-1 protein, which likely alter its 3-dimensional shape and impair its binding with microtubules.

It is unclear how DCTN1 gene mutations might increase susceptibility to amyotrophic lateral sclerosis. Impaired binding between the p150-glued version of dynactin-1 and microtubules may slow the transport of materials needed for the proper function of axons in motor neurons. Motor neurons are specialized nerve cells in the brain and spinal cord that control muscle movement. The decline and death of motor neurons is a characteristic feature of amyotrophic lateral sclerosis.

other disorders - associated with the DCTN1 gene

Researchers have identified at least one DCTN1 gene mutation that causes a nervous system disorder called distal hereditary motor neuronopathy type VIIB. Signs and symptoms of this disorder first appear in early adulthood and include breathing difficulties and progressive weakness of muscles in the face and hands. Muscle weakness in the feet and legs develops later. The mutation that causes this disorder changes one of the amino acids used to make dynactin-1. Specifically, it replaces the amino acid glycine with the amino acid serine at protein position 59 (written as Gly59Ser). It is unclear how this mutation causes distal hereditary motor neuronopathy type VIIB. It may disturb interactions between the dynactin complex and microtubules, which would disrupt transport activities and impair the function of axons in motor neurons.

At least one other DCTN1 gene mutation is associated with a brain disorder called frontotemporal dementia, which occurs in mid- to late adulthood. This disorder is characterized by behavioral changes such as impulsiveness and outbursts of frustration. Changes in speech and language can also occur, such as problems using the correct word and difficulties with reading. The DCTN1 gene mutation associated with this disorder replaces the amino acid arginine with the amino acid lysine at protein position 1101 (written as Arg1101Lys). This mutation likely alters the 3-dimensional shape of dynactin-1, which may impair its binding with microtubules. The role of this mutation in frontotemporal dementia is unclear. Impaired binding between the p150-glued version of dynactin-1 and microtubules may slow the transport of materials needed for the proper function of axons and the efficient transmission of nerve impulses.