Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation.

During brain development, the nucleus of migrating neurons follows the centrosome and translocates into the leading process. Defects in these migratory events, which affect neuronal migration, cause lissencephaly and other neurodevelopmental disorders. However, the mechanism of nuclear translocation remains elusive. Using whole exome sequencing (WES), we identified a novel nonsense BICD2 variant p.(Lys775Ter) (K775X) from a lissencephaly patient. Interestingly, most BICD2 missense variants have been associated with human spinal muscular atrophy (SMA) without obvious brain malformations. By in utero electroporation, we showed that BicD2 knockdown in mouse embryos inhibited neuronal migration. Surprisingly, we observed severe blockage of neuronal migration in cells overexpressing K775X but not in those expressing wild-type BicD2 or SMA-associated missense variants. The centrosome of the mutant was, on average, positioned farther away from the nucleus, indicating a failure in nuclear translocation without affecting the centrosome movement. Furthermore, BicD2 localized at the nuclear envelope (NE) through its interaction with NE protein Nesprin-2. K775X variant disrupted this interaction and further interrupted the NE recruitment of BicD2 and dynein. Remarkably, fusion of BicD2-K775X with NE-localizing domain KASH resumed neuronal migration. Our results underscore impaired nuclear translocation during neuronal migration as an important pathomechanism of lissencephaly.

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

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.