PAFAH1B1 – Lissencephaly Spectrum Disorders

PAFAH1B1 (LIS1) encodes a microtubule-associated protein critical for neuronal migration. Heterozygous loss-of-function variants in PAFAH1B1 cause lissencephaly spectrum disorders, characterized by smooth brain surface (agyria/pachygyria) and severe developmental delay. This association is well recognized in both isolated lissencephaly sequence and Miller-Dieker syndrome phenotypes.

Classical autosomal dominant inheritance of PAFAH1B1 variants has been demonstrated across multiple cohorts. In a landmark study of 90 probands, deletions or submicroscopic deletions of the 17p13.3 region including PAFAH1B1 were detected in 92% of Miller-Dieker syndrome cases and 38% of classical isolated lissencephaly sequence cases, implicating haploinsufficiency as the predominant pathogenic mechanism ([PMID:7907669]). Further analysis of 12 Japanese patients identified intragenic mutations and deletions in 50% of isolated lissencephaly sequence cases, confirming a high mutation rate in PAFAH1B1 ([PMID:9860301]).

The variant spectrum includes whole‐gene and exon deletions, frameshift insertions/deletions, nonsense variants, splice-site changes, and rare missense mutations. Approximately 40% of isolated posterior pachygyria patients harbor genomic deletions detectable by FISH or MLPA, while the remainder carry intragenic loss-of-function alleles ([PMID:11261426]). Recurrent frameshift variants such as c.162del (p.Lys54fs) and splice mutations are reported worldwide, supporting genetic testing strategies prioritizing both copy number and sequencing assays.

Case reports further illustrate phenotypic breadth. A Chinese family with autosomal dominant inheritance exhibited a novel missense variant c.412G>A (p.Glu138Lys) in PAFAH1B1 that cosegregated in three affected members presenting mild lissencephaly with basal ganglia calcification; the variant was absent in 200 controls and located within a conserved domain ([PMID:30100227]). De novo intronic and structural variants, including heterozygous inversions disrupting PAFAH1B1, have been identified by whole-genome sequencing in sporadic pachygyria ([PMID:39709006]).

Functional studies support a haploinsufficiency mechanism. In vitro assays of LIS1 point and truncation mutations demonstrate impaired folding and reduced association with microtubules. Phosphorylation of LIS1 regulates its microtubule binding, and CKII phosphorylates LIS1 on serine residues ([PMID:10583396]). In Lis1+/– mice, heterozygosity leads to defective neuronal migration, cortical layering abnormalities, impaired rotarod performance, and spatial learning deficits, mirroring human disease ([PMID:10541472]).

Collectively, genetic and experimental data provide definitive evidence for PAFAH1B1 haploinsufficiency as a cause of lissencephaly spectrum disorders. Routine clinical testing should include both deletion analysis and sequencing of PAFAH1B1 for early diagnosis and genetic counseling. Key take-home: PAFAH1B1 loss-of-function underlies autosomal dominant lissencephaly, with robust genotype–phenotype and functional concordance supporting precise molecular diagnostics.

References

• JAMA • 1993 • Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. PMID:7907669
• Human genetics • 1998 • Alteration of the LIS1 gene in Japanese patients with isolated lissencephaly sequence or Miller-Dieker syndrome. PMID:9860301
• Brain & development • 2019 • Identification of a novel PAFAH1B1 missense mutation as a cause of mild lissencephaly with basal ganglia calcification. PMID:30100227
• European journal of biochemistry • 1999 • Analysis of lissencephaly-causing LIS1 mutations. PMID:10583396
• Learning & memory • 1999 • Impaired learning and motor behavior in heterozygous Pafah1b1 (Lis1) mutant mice. PMID:10541472

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