FKTN

The FKTN gene (formerly known as FCMD) provides instructions for making a protein called fukutin. This protein is present in many of the body's tissues but is particularly abundant in muscles used for movement (skeletal muscles), the heart, and the brain.

Although the exact function of fukutin is unclear, researchers predict that it may chemically modify a protein called alpha (α)-dystroglycan. Specifically, fukutin is thought to add chains of sugar molecules to α-dystroglycan through a process known as glycosylation. Glycosylation is critical for the normal function of α-dystroglycan.

The α-dystroglycan protein helps anchor the structural framework inside each cell (cytoskeleton) with the lattice of proteins and other molecules outside the cell (extracellular matrix). In skeletal muscles, glycosylated α-dystroglycan helps stabilize and protect muscle fibers. In the brain, it helps direct the movement (migration) of nerve cells (neurons) during early development.

Fukuyama congenital muscular dystrophy - caused by mutations in the FKTN gene

Fukuyama congenital muscular dystrophy is seen almost exclusively in Japan. Virtually everyone with this condition has at least one copy of the same mutation, an insertion of about 3,000 extra DNA building blocks (3 kilobases) in the FKTN gene. This insertion occurs in a part of the gene known as the 3' untranslated region, which helps regulate the gene's activity. Researchers believe that the three-kilobase insertion reduces the amount of fukutin protein that is produced from the gene.

A shortage of fukutin likely prevents the normal glycosylation of α-dystroglycan. As a result, α-dystroglycan can no longer effectively anchor cells to the proteins and other molecules that surround them. Without functional α-dystroglycan to stabilize muscle cells, muscle fibers become damaged as they repeatedly contract and relax with use. The damaged fibers weaken and die over time, which affects the development, structure, and function of skeletal muscles in people with Fukuyama congenital muscular dystrophy.

Defective α-dystroglycan also affects the migration of neurons during the early development of the brain. Instead of stopping when they reach their intended destinations, some neurons migrate past the surface of the brain into the fluid-filled space that surrounds it. Researchers believe that this problem with neuronal migration causes a brain abnormality called cobblestone lissencephaly, in which the surface of the brain appears bumpy and irregular. Less is known about the effects of FKTN mutations in other parts of the body.

other disorders - caused by mutations in the FKTN gene

Mutations in the FKTN gene cause several other disorders affecting skeletal muscles and the heart. Unlike Fukuyama congenital muscular dystrophy, which is mostly limited to the Japanese population, these conditions have been described in several populations worldwide.

FKTN mutations have been identified in a small number of people with the characteristic features of Walker-Warburg syndrome, a very severe form of congenital muscular dystrophy. This condition is similar to Fukuyama congenital muscular dystrophy, but affected individuals have more severe eye abnormalities and live only into infancy or early childhood. Mutations in the FKTN gene have also been found in a few families with a less severe form of muscular dystrophy known as limb-girdle muscular dystrophy type 2M (LGMD2M). This condition causes muscle weakness but does not affect the brain.

Several people with a heart condition called dilated cardiomyopathy have been found to have mutations in the FKTN gene. This condition weakens and enlarges the heart, preventing it from pumping blood efficiently. When dilated cardiomyopathy is associated with FKTN mutations, it is known as type 1X (DCM1X). In addition to heart problems, some people with dilated cardiomyopathy type 1X have experienced mild muscle weakness beginning in adulthood.

FKTN mutations that prevent the production of any functional fukutin protein cause Walker-Warburg syndrome, the most severe condition associated with mutations in this gene. Changes in FKTN that reduce but do not eliminate the production of fukutin lead to somewhat less severe medical problems, such as those seen in limb-girdle muscular dystrophy type 2M and dilated cardiomyopathy type 1X.