In-frame deletion variant of ABCD1 in a sporadic case of adrenoleukodystrophy
HGV Database
The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9.figshare.hgv.3482.
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The Marchantia polymorpha pangenome reveals ancient mechanisms of plant adaptation to the environment
Plant adaptation to terrestrial life started 450 million years ago and has played a major role in the evolution of life on Earth. The genetic mechanisms allowing this adaptation to a diversity of terrestrial constraints have been mostly studied by focusing on flowering plants. Here, we gathered a collection of 133 accessions of the model bryophyte Marchantia polymorpha and studied its intraspecific diversity using selection signature analyses, a genome–environment association study and a pangenome. We identified adaptive features, such as peroxidases or nucleotide-binding and leucine-rich repeats (NLRs), also observed in flowering plants, likely inherited from the first land plants. The M. polymorpha pangenome also harbors lineage-specific accessory genes absent from seed plants. We conclude that different land plant lineages still share many elements from the genetic toolkit evolved by their most recent common ancestor to adapt to the terrestrial habitat, refined by lineage-specific polymorphisms and gene family evolution.
Enhanced osteogenic potential of iPSC-derived mesenchymal progenitor cells following genome editing of GWAS variants in the RUNX1 gene
Recent genome-wide association studies (GWAS) identified 518 significant loci associated with bone mineral density (BMD), including variants at the RUNX1 locus (rs13046645, rs2834676, and rs2834694). However, their regulatory impact on RUNX1 expression and bone formation remained unclear. This study utilized human induced pluripotent stem cells (iPSCs) differentiated into osteoblasts to investigate these variants’ regulatory roles. CRISPR/Cas9 was employed to generate mutant (Δ) iPSC lines lacking these loci at the RUNX1 locus. Deletion lines (Δ1 and Δ2) were created in iPSCs to assess the effects of removing regions containing these loci. Deletion lines exhibited enhanced osteogenic potential, with increased expression of osteogenic marker genes and Alizarin Red staining. Circularized chromosome conformation capture (4C-Seq) was utilized to analyze interactions between BMD-associated loci and the RUNX1 promoter during osteogenesis. Analysis revealed altered chromatin interactions with multiple gene promoters including RUNX1 isoform, as well as SETD4, a histone methyltransferase, indicating their regulatory influence. Interestingly, both deletion lines notably stimulated the expression of the long isoform of RUNX1, with more modest effects on the shorter isoform. Consistent upregulation of SETD4 and other predicted targets within the Δ2 deletion suggested its removal removed a regulatory hub constraining expression of multiple genes at this locus. In vivo experiments using a bone defect model in mice demonstrated increased bone regeneration with homozygous deletion of the Δ2 region. These findings indicate that BMD-associated variants within the RUNX1 locus regulate multiple effector genes involved in osteoblast commitment, providing valuable insights into genetic regulation of bone density and potential therapeutic targets.
LolA and LolB are conserved in Bacteroidota and are crucial for gliding motility and Type IX secretion
Lipoproteins are key outer membrane (OM) components in Gram-negative bacteria, essential for functions like membrane biogenesis and virulence. Bacteroidota, a diverse and widespread phylum, produce numerous OM lipoproteins that play vital roles in nutrient acquisition, Type IX secretion system (T9SS), and gliding motility. In Escherichia coli, lipoprotein transport to the OM is mediated by the Lol system, where LolA shuttles lipoproteins to LolB, which anchors them in the OM. However, LolB homologs were previously thought to be limited to γ- and β-proteobacteria. This study uncovers the presence of LolB in Bacteroidota and demonstrates that multiple LolA and LolB proteins co-exist in various species. Specifically, in Flavobacterium johnsoniae, LolA1 and LolB1 transport gliding motility and T9SS lipoproteins to the OM. Notably, these proteins are not interchangeable with their E. coli counterparts, indicating functional specialization. Some lipoproteins still localize to the OM in the absence of LolA and LolB, suggesting the existence of alternative transport pathways in Bacteroidota. This points to a more complex lipoprotein transport system in Bacteroidota compared to other Gram-negative bacteria. These findings reveal previously unrecognized lipoprotein transport mechanisms in Bacteroidota and suggest that this phylum has evolved unique strategies to manage the essential task of lipoprotein localization.
Wilson disease (novel ATP7B variants) with concomitant FLNC-related cardiomyopathy
We report a case of Wilson disease (WD) with dilated cardiomyopathy in which whole-genome sequencing (WGS) revealed the rare co-occurrence of two novel compound heterozygous ATP7B pathogenic variants (NM_001005918.3:c.2250del/p.N751Tfs*9 and c.3496C>T/p.L1166F) and a known FLNC pathogenic variant. Our results highlight the usefulness of WGS, even in the diagnosis of well-characterized genetic diseases such as WD.
Missense BICD2 variants in fetuses with congenital arthrogryposis and pterygia
Type 2 spinal muscular atrophy with lower extremity dominance (SMALED2) is caused by bicaudal D cargo adaptor 2 (BICD2) variants. However, the SMALED2 genotype and phenotype correlation have not been thoroughly characterized. We identified de novo heterozygous BICD2 missense variants in two fetuses with severe, prenatally diagnosed multiple arthrogryposis congenita. This report provides further insights into the genetics of this rare disease.
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