PAFAH1B1 gene

platelet activating factor acetylhydrolase 1b regulatory subunit 1

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 in the brain, a process known as neuronal migration. Proper neuronal migration is essential for normal brain development and function.

Separate from its role in the PAFAH1B complex, the PAFAH1B1 protein is also likely involved in the organization of the cell's structural framework (the cytoskeleton). This protein interacts with microtubules and regulates a variety of proteins that are involved in their function. Microtubules are rigid, hollow fibers that make up the cytoskeleton, and they are involved in cell division and movement.

More than 70 mutations in the PAFAH1B1 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 the PAFAH1B1 gene mutations that cause ILS lead to the production of an abnormally small, nonfunctional version of the PAFAH1B1 protein. PAFAH1B1 gene mutations account for over half of all ILS cases.

As a result of PAFAH1B1 gene mutations, PAF levels are uncontrolled and the normal function of microtubules is impaired. Neurons in the developing brain are particularly affected, which impairs brain development and leads to the severe neurological problems characteristic of ILS.

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 epilepsy. A decrease in neuronal migration caused by a lack of PAFAH1B1 protein is responsible for the lissencephaly 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.

In some cases, PAFAH1B1 gene mutations are present in only some of the body's cells, a situation 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.

Cytogenetic Location: 17p13.3, which is the short (p) arm of chromosome 17 at position 13.3

Molecular Location: base pairs 2,593,210 to 2,685,617 on chromosome 17 (Homo sapiens Annotation Release 109, GRCh38.p12) (NCBI)

Cytogenetic Location: 17p13.3, which is the short (p) arm of chromosome 17 at position 13.3
  • LIS1
  • LIS2
  • lissencephaly 1 protein
  • MDCR
  • platelet-activating factor acetylhydrolase 1b, regulatory subunit 1 (45kDa)
  • platelet-activating factor acetylhydrolase, isoform Ib, alpha subunit
  • platelet-activating factor acetylhydrolase, isoform Ib, subunit 1 (45kDa)