The LIS1/PAFAH1B1gene is located on chromosome 17p13.3 and consists of nine exons. The LIS1/PAFAH1B1 gene encodes a 45-kDa protein (PAFAH1B1), which functions as a regulatory subunit of platelet-activating factor acetylhydrolase (PAF-AH). The PAFAH1B1 protein is required during brain development for the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. LIS1/PAFAH1B1 related LIS is more severe in the posterior brain regions (p>a gradient). About 60% of patients with p>a isolated LIS (ILS) carry genomic alterations or mutations involving LIS1/PAFAH1B1. Most mutations (84%) are truncating. Small genomic deletions and duplications of LIS1/PAFAH1B1 occur in almost 50% of patients. The type and position of mutations of LIS1/PAFAH1B1 do not appear to correlate with the phenotype. A simplified gyral pattern in the posterior brain, with underlying SBH, has been associated with mosaic mutations of LIS1/PAFAH1B1.
Miller–Dieker syndrome is caused by deletion of LIS1/PAFAH1B1 and contiguous genes in the 17p13.3 region. Deletion of two additional genes, CRK and YWHAE, telomeric to LIS1/PAFAH1B1, may contribute to the most severe LIS grade and dysmorphic features in this syndrome.