TUBA1A

Approximately 40 mutations in the TUBA1A gene have been found to cause isolated lissencephaly sequence (ILS). This condition is characterized by abnormal brain development that results in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. Individuals with ILS have severe neurological problems, including intellectual disability and recurrent seizures (epilepsy). Most of these mutations change single protein building blocks (amino acids) in the α-tubulin protein. The resulting abnormal α-tubulin cannot form microtubules or interact with other proteins. As a result, the overall function of microtubules is reduced. In the developing brain, this decrease in microtubule function impairs the normal migration of neurons and leads to a decrease in the formation of the brain's folds and grooves or a completely smooth appearance of the brain, resulting in the neurological problems characteristic of ILS.

At least 10 mutations in the TUBA1A gene have been found to cause lissencephaly with cerebellar hypoplasia (LCH). This condition affects brain development, resulting in lissencephaly and an unusually small and underdeveloped area of the brain called the cerebellum (cerebellar hypoplasia). The TUBA1A gene mutations that cause LCH change single amino acids in the α-tubulin protein. These altered proteins can still be incorporated into microtubules, but research suggests that these microtubules have decreased or abnormal function.

In the developing brain, impaired microtubule function prevents the normal migration of neurons. As a result, the normal folds and grooves of the brain do not form and the cerebellum and other brain structures do not develop properly. This impairment of brain development leads to intellectual disability, delayed overall development, movement problems, and other signs and symptoms of LCH.