Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.

TitlePathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.
Publication TypeJournal Article
Year of Publication2020
AuthorsTsai, M-H, Muir, AM, Wang, W-J, Kang, Y-N, Yang, K-C, Chao, N-H, Wu, M-F, Chang, Y-C, Porter, BE, Jansen, LA, Sebire, G, Deconinck, N, Fan, W-L, Su, S-C, Chung, W-H, Fuerte, EPAlmanza, Mehaffey, MG, Ng, C-C, Chan, C-K, Lim, K-S, Leventer, RJ, Lockhart, PJ, Riney, K, Damiano, JA, Hildebrand, MS, Mirzaa, GM, Dobyns, WB, Berkovic, SF, Scheffer, IE, Tsai, J-W, Mefford, HC
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
Date Published2020 04 22
KeywordsAdolescent, Adult, Age of Onset, Animals, Centrosome, Child, Child, Preschool, Chromosome Aberrations, Classical Lissencephalies and Subcortical Band Heterotopias, Cytoskeletal Proteins, Female, Gene Knockdown Techniques, Genetic Variation, Heterozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Mice, Mutation, Oncogene Proteins, Fusion, Pedigree, Seizures, Young Adult

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

Alternate JournalNeuron
PubMed ID32097630
PubMed Central IDPMC7357395
Grant ListP50 HD103524 / HD / NICHD NIH HHS / United States
R01 NS069605 / NS / NINDS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States