PAFAH1B1: Platelet Activating Factor Acetylhydrolase 1b Regulatory Subunit 1
A key regulator of neuronal migration and cortical development; mutations cause lissencephaly.
Gene Information Card
| Symbol | PAFAH1B1 |
|---|---|
| Full Name | Platelet Activating Factor Acetylhydrolase 1b Regulatory Subunit 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 17p13.3 |
| NCBI Gene ID | 5048 ncbi.nlm.nih.gov/gene/5048 |
| Ensembl ID | ENSG00000007168 |
| UniProt ID | P43034 |
| OMIM ID | 601545 |
| HGNC ID | 8575 |
| Aliases | LIS1, MDCR, PAFAH, LIS-1, PAFAHA |
Description
PAFAH1B1 encodes the non-catalytic regulatory subunit of platelet-activating factor acetylhydrolase 1b, a heterotrimeric enzyme that inactivates platelet-activating factor (PAF). The encoded protein, also known as LIS1, is essential for neuronal migration during brain development. It interacts with cytoplasmic dynein and microtubule-associated proteins to regulate nuclear positioning and cell motility. Heterozygous deletions or loss-of-function mutations cause lissencephaly type 1 (classic lissencephaly) and Miller-Dieker syndrome. The gene is also implicated in spermatogenesis and cancer cell migration.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Lissencephaly 1 (classic lissencephaly) | Haploinsufficiency of PAFAH1B1 disrupts neuronal migration, leading to smooth brain surface and abnormal cortical layering. | ClinVar, OMIM |
| Miller-Dieker syndrome | Contiguous gene deletion including PAFAH1B1 and adjacent genes (e.g., YWHAE) causes severe lissencephaly with distinct facial features. | OMIM, NCBI |
| Subcortical band heterotopia | Mosaic or milder mutations in PAFAH1B1 result in incomplete neuronal migration, forming heterotopic gray matter bands. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | High |
| Testis | 8.2 | Medium |
| Lung | 4.1 | Medium |
| Heart | 3.0 | Low |
| Liver | 1.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.3 | High expression; used in neuronal migration studies |
| HeLa (cervical carcinoma) | 6.8 | Moderate expression |
| A549 (lung carcinoma) | 4.2 | Moderate expression |
| HEK293 (embryonic kidney) | 3.1 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.73C>T (p.Arg25Ter) | Nonsense | Rare | Loss of function; associated with lissencephaly |
| c.817G>A (p.Gly273Ser) | Missense | Rare | Reduced dynein binding; causes subcortical band heterotopia |
| c.949_950del (p.Leu317ValfsTer3) | Frameshift | Rare | Premature truncation; severe lissencephaly |
| Whole gene deletion | Copy number loss | Common in Miller-Dieker | Haploinsufficiency; contiguous gene syndrome |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic mutations (nonsense, frameshift, deletions) lead to haploinsufficiency, reducing LIS1 protein levels and impairing dynein-mediated neuronal migration.
Gain of Function (GOF)
Not reported for PAFAH1B1; no activating mutations are known.
Dominant Negative (DN)
Some missense mutations (e.g., p.Gly273Ser) may produce a protein that interferes with wild-type LIS1 function, though haploinsufficiency is the primary mechanism.
View complete mutation data：
Gene Ontology (GO)
Pathways
• REACT:21369 - Dynein-mediated cargo transport
• REACT:111045 - Lissencephaly gene (LIS1) in neuronal migration
• WP:WP179 - Cytoplasmic dynein pathway
• KEGG:hsa05166 - Human T-cell leukemia virus 1 infection (dynein involvement)
Protein Summary
PAFAH1B1 (LIS1) is a 410-amino acid protein containing seven WD40 repeats that form a beta-propeller structure. It functions as a regulatory subunit of PAF acetylhydrolase 1b and as a critical cofactor for cytoplasmic dynein. LIS1 binds to dynein heavy chain and enhances its processivity, particularly under load. It also interacts with NUDC, NDE1, and NDEL1 to regulate microtubule organization, nuclear migration, and centrosome positioning. Loss of LIS1 disrupts neuronal migration, leading to lissencephaly. The protein is highly expressed in fetal brain and testis.
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