fukutin related protein
The FKRP gene provides instructions for making a protein called fukutin-related protein (FKRP). This protein is present in many of the body's tissues but is particularly abundant in muscles used for movement (skeletal muscles), the brain, and the heart. Within cells, FKRP is found in a specialized structure called the Golgi apparatus, where newly produced proteins are modified.
Although the exact function of FKRP is unclear, researchers predict that it may chemically modify a protein called alpha (α)-dystroglycan. Specifically, FKRP 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) to 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.
Genetics Home Reference provides information about limb-girdle muscular dystrophy.
Mutations in the FKRP gene cause Walker-Warburg syndrome in a small number of people. This condition is the most severe form of a group of disorders known as congenital muscular dystrophies. Walker-Warburg syndrome causes muscle weakness and abnormalities of the brain and eyes. Because of the severity of the problems caused by this condition, affected individuals usually do not survive past early childhood.
Many FKRP gene mutations involved in Walker-Warburg syndrome change single protein building blocks (amino acids) in FKRP. The altered proteins cannot reach the Golgi apparatus and are instead broken down, resulting in a reduction of functional FKRP.
A shortage of FKRP 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 Walker-Warburg syndrome.
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 lacks the normal folds and grooves and instead appears bumpy and irregular. Less is known about the effects of FKRP gene mutations in other parts of the body.
Mutations in the FKRP gene are also involved in less severe forms of muscular dystrophy. Limb-girdle muscular dystrophy type 2I (LGMD2I) is the mildest of the conditions caused by changes in this gene. Individuals with this condition have muscle weakness in the arms and legs that begins in childhood and causes difficulty walking. Some individuals with LGMD2I also have a heart condition called dilated cardiomyopathy that weakens and enlarges the heart, preventing it from pumping blood efficiently. Mutations in the FKRP gene have also been found in a small number of people with congenital muscular dystrophy type 1C (MDC1C), which causes muscle weakness, brain abnormalities, and intellectual disability but usually does not affect the eyes. It is unclear how mutations in this gene cause this range of muscular dystrophies.