Recurrent KIF2A mutations are responsible for classic lissencephaly
Mara Cavallin1,2, Emilia K Bijlsma3, Adrienne El Morjani4,5
1Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
Neurogenetics
|October 18, 2016
Summary
Mutations in KIF2A cause lissencephaly and microcephaly by disrupting microtubule dynamics. These findings highlight KIF2A as a significant genetic cause of these severe brain development disorders.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Kinesins are motor proteins crucial for microtubule organization, impacting neuronal development.
- KIF2A mutations have been linked to cortical malformations and microcephaly.
Observation:
- Two new patients with lissencephaly and microcephaly were identified with de novo mutations in KIF2A at Ser317 and His321.
- Re-evaluation of previous cases confirmed mutations at these specific residues, suggesting they are mutation hotspots.
Findings:
- The identified KIF2A mutations (p.Ser317Asn and p.His321Pro) result in classic lissencephaly with a posterior-to-anterior gradient.
- A significant proportion of patients (75%) also exhibited variable microcephaly, some as severe as -5 SD.
- These mutations are located in the KIF2A motor domain, likely impairing ATP binding/hydrolysis and microtubule depolymerization.
Implications:
- KIF2A mutations are a notable cause of classic lissencephaly with microcephaly.
- Understanding KIF2A's role in microtubule dynamics offers insights into neuronal migration and brain development.
- These findings expand the genetic landscape of lissencephaly and microcephaly syndromes.
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