Biology subjects

Chrast, J.

Publications and source records attributed to Chrast, J..

5 recordsLinked to original sources

bioRxiv2025

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.

genetics↗

bioRxiv2020

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

genetics↗

bioRxiv2019

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

genomics↗

bioRxiv2019

The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism patients

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy number variations, one of the most common genetic causes of autism. These copy number polymorphic duplications are under positive selection and include 3-8 copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, P=4e-7, OR=5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, with 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, we found an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, P=1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The deletion and Bola2-deficient mice showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc protoporphyrin to heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo and its expansion has a potential adaptive role in protecting against iron deficiency.

genetics↗

bioRxiv2017

Low Rate of Somatic Mutations in a Long-Lived Oak Tree

Because plants do not possess a proper germline, deleterious somatic mutations can be passed to gametes and a large number of cell divisions separating zygote from gamete formation in long-lived plants may lead to many mutations. We sequenced the genome of two terminal branches of a 234-year-old oak tree and found few fixed somatic single-nucleotide variants (SNVs), whose sequential appearance in the tree could be traced along nested sectors of younger branches. Our data suggest that stem cells of shoot meristems are robustly protected from accumulation of mutations in trees.

plant biology↗