Lipid transport is necessary for neocortical lamination

We previously described the Alkuraya-Kučinskas syndrome, a disorder associated with biallelic variants in BLTP1. Many probands die perinatally with corpus callosum agenesis, ventriculomegaly and arthrogryposis. Here, we describe ten novel patients and engineered conditional knockouts (cKO) in which Bltp1 expression is only removed in cortical and hippocampal neurons. Bltp1 cKOs recapitulated the preweaning lethality observed in the constitutional knockouts, suggesting that lack of BLTP1 expression in neurons is sufficient to cause death. Homozygous cKO presented a complete agenesis of the corpus callosum, a smaller anterior commissure, a malformed hippocampus and a reduced thickness of the cortical plate with a complete lack of defined structural layers and absence of radial glial and intermediate neural progenitors and mature neurons, respectively. As BLTP1 was shown to be a barrel-shaped tube containing lipids, we compared the amount of 429 lipids in the cKO and their control littermates' cortexes. We observed significant depletions of ether-linked phosphatidylethanolamines and triglycerides and accumulations of specific sphingomyelins and hexosylceramides in cKOs. Our results are consistent with the recent description of BLTP1 as a tubular protein that transports phospholipids between the endoplasmic reticulum and the plasma membrane. They suggest that non-vesicular lipid transport is essential for neocortical and cerebellar lamination.