2.1. Walker-Warburg syndrome

At least 24 mutations in the POMT1 gene have been found to cause Walker-Warburg syndrome, the most severe form of a group of disorders known as congenital muscular dystrophies. Individuals with Walker-Warburg syndrome have skeletal 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.

POMT1 gene mutations that cause Walker-Warburg syndrome lead to the formation of nonfunctional POMT enzyme complexes that cannot transfer mannose to α-dystroglycan, preventing its normal glycosylation. 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 the muscle fibers, they 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 POMT1 gene mutations in other parts of the body.

2.2. Other disorders

Mutations in the POMT1 gene are also involved in less severe forms of muscular dystrophy, including muscle-eye-brain disease and POMT1-related congenital muscular dystrophy (also known as MDDGB1). Muscle-eye-brain disease is similar to Walker-Warburg syndrome (described above), although affected individuals usually survive into childhood or adolescence. POMT1-related congenital muscular dystrophy causes muscle weakness, brain abnormalities, and intellectual disability, but usually does not affect the eyes.

POMT1 gene mutations that cause these conditions result in POMT enzyme complexes with reduced function. As a result, glycosylation of α-dystroglycan is impaired. The severity of the resulting condition appears to be related to the level of α-dystroglycan glycosylation; the less glycosylation, the more severe the condition.