PAFAH1B1

The PAFAH1B1 gene (also known as LIS1) provides instructions for making a protein that is one part (subunit) of a complex called platelet activating factor acetyl hydrolase 1B (PAFAH1B). In the brain, this complex regulates the level of a molecule called platelet activating factor (PAF). PAF is thought to be involved in directing the movement of nerve cells (neuronal migration) in the brain. Proper neuronal migration is essential for normal brain development and function.

The PAFAH1B1 protein promotes neuronal migration by interacting with structures called microtubules, as well as proteins involved in microtubule function. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules form a meshwork around the nucleus and, with the aid of other proteins, expand and contract the cytoskeleton to move the neuron.

Miller-Dieker syndrome - associated with the PAFAH1B1 gene

The characteristic signs and symptoms of Miller-Dieker syndrome are caused by a deletion of genetic material near the end of the short (p) arm of chromosome 17. The chromosomal region that is typically deleted contains multiple genes, including the PAFAH1B1 gene. As a result of the deletion, people with this condition have only one copy of the PAFAH1B1 gene in each cell instead of the usual two copies.

A deletion of one copy of the PAFAH1B1 gene in each cell reduces the amount of PAFAH1B1 protein by about half. Researchers believe that a shortage of this protein is responsible for many of the features of Miller-Dieker syndrome, including intellectual disability, developmental delay, and recurrent seizures (epilepsy). A decrease in neuronal migration caused by a lack of PAFAH1B1 protein is responsible for the lissencephaly (a problem with brain development in which the surface of the brain is abnormally smooth) that is characteristic of Miller-Dieker syndrome.

Other genes deleted in the same region of chromosome 17 are responsible for the other features of Miller-Dieker syndrome such as distinctive facial features, slow growth, and breathing difficulties.

other disorders - caused by mutations in the PAFAH1B1 gene

Mutations in the PAFAH1B1 gene can cause lissencephaly without any other signs or symptoms. When lissencephaly occurs without any other features, it is called isolated lissencephaly sequence (ILS). Characteristic features of ILS include severe intellectual disability and developmental delay, seizures, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties.

PAFAH1B1 gene mutations that cause ILS include small deletions or insertions of genetic material as well as changes in single building blocks of protein (amino acids). Mutations that cause a premature stop signal in the instructions for making the PAFAH1B1 protein can also cause ILS.

A few people have had PAFAH1B1 gene mutations in only some of the body's cells, which is known as mosaicism. Mosaicism for PAFAH1B1 gene mutations causes a less severe brain abnormality called subcortical band heterotopia. This abnormality occurs when neurons migrate to an area of the brain where they are not supposed to be (heterotopia), and form abnormal band-like clusters. Since these bands are located beneath the cerebral cortex, they are said to be subcortical. The signs and symptoms of subcortical band heterotopia vary from severe intellectual disability and epilepsy to normal intelligence with mild or no epilepsy.