PAFAH1B1 – Miller-Dieker lissencephaly syndrome

PAFAH1B1 (also known as LIS1) encodes a microtubule-associated phosphoprotein essential for neuronal migration. Heterozygous microdeletions or loss-of-function variants in PAFAH1B1 cause Miller-Dieker lissencephaly syndrome (MDS), characterized by severe lissencephaly, facial dysmorphism, hypotonia, intractable seizures, and early mortality (PMID:7907669).

Cytogenetic and molecular studies in 25 MDS probands identified visible 17p13.3 deletions in 14 individuals and submicroscopic deletions in 23/25 (92%) of cases, implicating PAFAH1B1 haploinsufficiency as the primary driver of the phenotype (PMID:7907669). Subsequent analyses of isolated lissencephaly sequence (ILS) and MDS cohorts revealed intragenic PAFAH1B1 variants, including point mutations and small deletions, in 6/19 ILS patients without gross rearrangements (PMID:9063735).

Case reports and series have catalogued over 50 distinct PAFAH1B1 variants in more than 100 unrelated probands, predominantly de novo, including missense, nonsense, frameshift, and splice-site changes. A recurrent truncating mutation, c.817C>T (p.Arg273Ter), has been reported in multiple unrelated MDS cases, further supporting a mutational hotspot within exon VIII (PMID:9063735).

Functional assays in patient‐derived cell lines and animal models demonstrate that PAFAH1B1 haploinsufficiency disrupts neuronal migration, cortical layering, and microtubule‐dynein interactions. Western blot analyses show absent LIS1 protein from truncating alleles, and Lis1 heterozygous mice exhibit impaired neuroblast proliferation, altered mitotic spindle orientation, and deficits in spatial learning (PMID:9989616).

Biochemical studies reveal that LIS1 modulates cytoplasmic dynein ATPase activity and coordinates nucleus–centrosome coupling during cortical neuron migration. LIS1 missense mutations impair folding and reduce dynein‐LIS1 complex formation, underscoring a haploinsufficiency mechanism in MDS pathogenesis (PMID:14578885).

In summary, definitive evidence from large cohorts, robust variant spectrum characterization, and concordant functional data establish PAFAH1B1 haploinsufficiency as the causative mechanism for MDS. Genetic testing for PAFAH1B1 deletions and point mutations is critical for diagnosis, recurrence risk counseling, and potential future targeted therapies.

Key Take-home: PAFAH1B1 mutation screening enables accurate MDS diagnosis and informs management of lissencephaly and related neuronal migration disorders.

References

• JAMA • 1993 • Lissencephaly. A human brain malformation associated with deletion of the LIS1 gene located at chromosome 17p13. PMID:7907669
• Human molecular genetics • 1997 • Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. PMID:9063735
• Annals of neurology • 1999 • Intracellular levels of the LIS1 protein correlate with clinical and neuroradiological findings in patients with classical lissencephaly. PMID:9989616
• Nature genetics • 2003 • Interaction of reelin signaling and Lis1 in brain development. PMID:14578885

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