[^1]
| Symbol |
PAFAH1B1 |
| Full Name |
Platelet Activating Factor Acetylhydrolase 1B Subunit 1 (LIS1) |
| Chromosome |
17p13.3 |
| NCBI Gene |
5099 |
| Ensembl |
ENSG00000007174 |
| OMIM |
601545 |
| UniProt |
P43004 |
| Diseases |
[Lissencephaly](/diseases/lissencephaly), [Miller-Dieker Syndrome](/diseases/miller-dieker-syndrome), [Alzheimer's Disease](/diseases/alzheimers) |
| Expression |
Ubiquitously expressed; high expression in brain, particularly [neurons](/entities/neurons) |
PAFAH1B1 (Platelet Activating Factor Acetylhydrolase 1B Subunit 1), also known as LIS1, is a gene located on chromosome 17p13.3 that encodes a regulatory subunit of platelet-activating factor acetylhydrolase (PAFAH). PAFAH1B1 is a critical regulator of neuronal migration and cortical development. Mutations cause lissencephaly (smooth brain), a severe developmental brain malformation, and the gene has also been implicated in Alzheimer's disease and other neurological conditions [1][2].
The PAFAH1B1 gene spans approximately 65 kb and consists of 11 exons. The gene encodes a 410-amino acid protein that functions in multiple cellular pathways.
- Chromosome: 17p13.3
- Location: chr17: 2590752-2743601
- Strand: Plus strand
- Exons: 11
The gene is located in the Miller-Dieker syndrome critical region on chromosome 17p13.3.
¶ Protein Structure and Function
¶ Domain Architecture
PAFAH1B1 contains:
- WD40 repeat domain: Forms beta-propeller structure for protein-protein interactions
- N-terminal region: Dimerization and regulatory functions
- C-terminal region: Interaction with dynein/dynactin complex
- Dynein regulation: PAFAH1B1 regulates the dynein-dynactin motor complex
- Cortical development: Essential for neuronal migration during corticogenesis
- Axonal guidance: Involved in axonal pathfinding
- Cytoplasmic signaling: Modulates various signaling pathways
- PAFAH enzymatic activity: Regulatory subunit of platelet-activating factor acetylhydrolase
- Microtubule organization: Regulates microtubule dynamics
- Organelle transport: Involved in intracellular trafficking
PAFAH1B1 mutations are the most common cause of lissencephaly:
Classic Lissencephaly:
- Smooth brain surface due to failed neuronal migration
- Severe intellectual disability
- Epilepsy
- Hypotonia followed by spasticity
Miller-Dieker Syndrome:
- Lissencephaly with additional features
- Facial dysmorphism
- Severe developmental delay
- Often lethal in infancy
Pathogenic variants:
- Heterozygous deletions (most common)
- Missense mutations
- Nonsense and frameshift mutations
- Mutations are typically de novo
Recent research implicates PAFAH1B1 in Alzheimer's disease:
- Dynein dysfunction: Impairs axonal transport in AD
- Amyloid processing: May affect APP trafficking
- Tau pathology: Linked to tau phosphorylation and spread
- Neuronal vulnerability: May increase neuronal susceptibility to degeneration
- Periventricular heterotopia: Some variants cause neuronal heterotopia
- Epilepsy: Associated with seizure disorders
- Neurodevelopmental disorders: Various developmental delays
PAFAH1B1 is ubiquitously expressed with highest levels in:
- Brain (cerebral cortex, hippocampus)
- Lung
- Liver
- Kidney
- Testis
- Cytoplasmic localization
- Associates with microtubules
- Enriched in growth cones
PAFAH1B1 expression is regulated during:
- Brain development
- Cell cycle
- Various signaling pathways
- Gene therapy: Viral vector delivery of functional PAFAH1B1
- Protein replacement: Targeting to restore function
- Symptomatic management: Seizure control, supportive care
- Understanding PAFAH1B1's role in neurodegeneration
- Developing therapies for lissencephaly
- Exploring axonal transport modulation in AD
- PAFAH1B1 mutations cause lissencephaly. Nature Genetics, 1998.
- LIS1 and dynein: a molecular framework for neuronal migration. Trends in Neurosciences, 2011.
- PAFAH1B1 dysfunction in Alzheimer's disease. Neurobiology of Aging, 2020.