Lipid transport is necessary for neocortical lamination
We previously described the Alkuraya-Ku[c]inskas syndrome, a disorder associated with biallelic variants in BLTP1 (bridge-like lipid transfer protein), a.k.a. KIAA1109. The majority of probands die perinatally with corpus callosum agenesis, ventriculomegaly and arthrogryposis. Homozygous ablation of mouse Bltp1 resulted in similar preweaning lethality. Here, we describe ten novel patients expanding the characterization of this syndrome at the mild end of the phenotypic spectrum. To model this syndrome, we engineered Emx1-Cre-mediated conditional knockouts (cKO) in which Bltp1 expression is only removed in cortical and hippocampal neurons. This restricted ablation of Bltp1 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. As BLTP1 was shown to be a barrel-shaped tube containing lipids, we compared the amount of lipid species in the cKO and their control littermates cortexes. We observed significant depletions of ether-linked phosphatidylethanolamines and triglycerides and accumulations of 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. Consistent with a BLTP1 role in cortex development we show that heterozygous carriers of a BLTP1 truncation variant presented a decrease in peripheral cortical grey matter suggesting an autosomal dominant inheritance pattern beside the already described autosomal recessive.