Lipid transport is necessary for neocortical lamination

ABSTRACT We previously described the Alkuraya-Kučinskas 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.

Authors

Institutions

Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2025-12-09
DOI
https://doi.org/10.64898/2025.12.05.692589
Primary Topic
Genetic and Kidney Cyst Diseases
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Lipid transport is necessary for neocortical lamination

Fabrizio Vacca, Olivier Musset, Stephan C. Collins, Lucie Gueneau et al.
bioRxiv (Cold Spring Harbor Laboratory)
Genetic and Kidney Cyst Diseases
article

Lipid transport is necessary for neocortical lamination

Fabrizio Vacca, Olivier Musset, Stephan C. Collins, Lucie Gueneau, Alexandre Reymond, Frédéric Tran Mau‐Them, Catarina Olimpio, Anna Jansen, Manju A. Kurian, Matthew Pastore, Binnaz Yalcin, Yann Emmenegger, Catherine Roger, Kristen Truxal, Jessica Rosenblum, Marijn F. Stokman, Matthew A. Deardorff, Ana Perez Caballero, Nicolas Guex, Andreas Busche, Fabienne Allias, Muhammad Ansar, Kiarash Sadrieh, Ben Paternoster, Serpil Alkan, Linda Rossetti, Zoltán Kutalik, L. Walker, Julijana Ivanišević, Jane Hassell, Jean‐Hubert Caberg, Héctor Gallart‐Ayala, Oliver Klaas, Chiara Auwerx, Judit Horváth, Daniel C. Koboldt, Jacqueline Chrast, Marije Meuwissen, Stephanie Baskin, Nicolas Goss, Siwar Ben-Ayache, Pauline Rogg
article en

Abstract

ABSTRACT We previously described the Alkuraya-Kučinskas 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.

bioRxiv (Cold Spring Harbor Laboratory)
Nationwide Children's Hospital (US), Children's Hospital of Los Angeles (US), Radboud University Nijmegen (NL), Université de Bourgogne (FR), Baylor College of Medicine (US), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Radboud University Medical Center (NL), Hospices Civils de Lyon (FR), Antwerp University Hospital (BE), University Hospital Münster (DE), Radboud Institute for Molecular Life Sciences (NL), Wessex Regional Genetics Laboratory (GB), Helen DeVos Children's Hospital (US), Centre Hospitalier Universitaire de Liège (BE), University College London (GB), University of Lausanne (CH)
Openalex Percentile: Top 59%
Genetic and Kidney Cyst Diseases
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.