LIS1

LIS1, also known as lissencephaly-1 protein or PAFAH1B1, is a conserved protein encoded by the PAFAH1B1 gene in humans. The gene is located on chromosome 17p13.3. LIS1 is a WD40-repeat protein that functions as a regulator of the cytoplasmic dynein motor complex, influencing dynein-driven transport along microtubules. It interacts with dynein and dynactin and modulates motor activity and cargo movement, with important roles in both cellular division and intracellular trafficking.

In the developing brain, LIS1 is essential for neuronal migration, particularly for nucleokinesis—the movement of the neuronal nucleus within migrating neurons. By regulating dynein-based forces, LIS1 supports proper layering of the cerebral cortex. It also has roles in mitosis, including spindle orientation and progression through cell division, reflecting its broader involvement in dynein-dependent processes.

Genetically, mutations or deletions of PAFAH1B1 cause lissencephaly type 1, a severe brain malformation characterized by abnormal cortical organization, reduced cortical gyration (agyria or pachygyria), seizures, hypotonia, and developmental delay. Haploinsufficiency of LIS1 is a common cause of this condition and can be inherited in an autosomal dominant pattern with variable expressivity. In model organisms, loss of LIS1 disrupts dynein function and impairs neuronal migration and brain development, corroborating its central role in dynein regulation.

Beyond brain development, LIS1’s influence on dynein suggests broader contributions to cellular processes that depend on microtubule-based transport. Clinically, PAFAH1B1 genetic testing is used in the diagnosis of suspected lissencephaly and related migration disorders.