Biology subjects

Dubourg, C.

Publications and source records attributed to Dubourg, C..

5 recordsLinked to original sources

bioRxiv2025

Mapping the temporal and functional landscape of Sonic Hedgehog signaling reveals new insights into early human forebrain development

The early patterning of the anterior neuroectoderm constitutes a fundamental blueprint for human brain development, orchestrated by multiple signaling pathways. Among them, Sonic Hedgehog (SHH) plays a key influence. However, the transcriptional programs it engages remain poorly defined due to the limited accessibility of human brain tissue. To address this, we established a human induced pluripotent stem cells-derived model of early forebrain differentiation, enabling a precise dissection of SHH-driven transcriptional programs over time. RNA sequencing revealed dynamic transcriptomic landscapes governing forebrain neuroectoderm specification and dorsoventral patterning. In addition, pharmacological perturbation of SHH signaling allowed to identify an extended collection of novel forebrain regionalization markers, including several previously unrecognized dorsal and ventral determinants. By combining in vivo human datasets with functional mouse studies, we enhanced the biological relevance of this extended network of putative SHH-regulated genes and long non-coding RNAs in shaping early forebrain architecture. This work advances our understanding of the temporal dynamics of SHH signaling in human neurodevelopment and provide critical molecular insights into midline brain malformations. It offers a promising foundation for advancing molecular diagnosis of complex rare genetic disorders. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/654466v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@dac307org.highwire.dtl.DTLVardef@3a051borg.highwire.dtl.DTLVardef@12559c9org.highwire.dtl.DTLVardef@129cbec_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Gene editing is suitable to treat GM1 Gangliosidosis: a proof-of-concept study

Ganglioside-monosialic acid (GM1) gangliosidosis, a rare autosomal recessive disorder, is frequently caused by deleterious single nucleotide variants (SNVs) in GLB1 gene. These variants result in reduced {beta}-galactosidase ({beta}-gal) activity, leading to neurodegeneration associated with premature death. Currently, no effective therapy for GM1 gangliosidosis is available. Three ongoing clinical trials aim to deliver a functional copy of the GLB1 gene to stop disease progression. Here, we show that 41% of GLB1 pathogenic SNVs might be cured by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring a therapeutic level of {beta}-gal activity. Unbiased off-target DNA analysis did not detect off-target editing activity in treated patients cells except a bystander edit without consequences on {beta}-gal activity. Altogether our results suggest that gene editing is an alternative strategy to cure GM1 gangliosidosis, by correcting the root cause of disease and avoiding repetitive adeno-associated virus injections.

genetics↗

bioRxiv2020

The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms

The rise of pangenomic molecular assays allowed uncovering complex rearrangements named chromoanagenesis that were hypothesized to result from catastrophic shattering events. Constitutional cases have typically been reported individually preventing identification of common features and uncovering the mechanisms at play. We characterized 20 new chromoanagenesis and discovered yet undescribed features. While literature differentiates chromothripsis and its shattering event repaired through non-homologous end joining from chromoanasynthesis born to aberrant replicative processes, we identified shattered chromosomes repaired through a combination of mechanisms. In particular, three samples present with "rearrangement hubs" comprising a fragmented kilobase-long sequence threaded throughout the rearrangement. To assess the mechanisms at play, we merged our data with those of 20 published constitutional complex chromosomal rearrangement cases. We evaluated if the distribution of their 1032 combined breakpoints was distinctive using bootstrap simulations and found that breakpoints tend to keep away from haplosensitive genes suggesting selective pressure. We then compared their distribution with that of 13,310 and 468 breakpoints of cancer complex chromosomal rearrangements and constitutional simple rearrangement samples, respectively. Both complex rearrangement groups showed breakpoint enrichment in late replicating regions suggesting similar origins for constitutional and cancer cases. Simple rearrangement breakpoints but not complex ones were depleted from lamina-associated domains (LADs), possibly as a consequence of reduced mobility of DNA ends bound to lamina. The enrichment of breakpoints in late-replicating chromatin for both constitutional and cancer chromoanagenesis provides an orthogonal support to the premature chromosome condensation hypothesis that was put forward to explain chromoanagenesis.

genomics↗

bioRxiv2019

Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

genetics↗

bioRxiv2018

Integrated Clinical and Omics Approach to Rare Diseases: Novel Genes and Oligogenic Inheritance in Holoprosencephaly

PurposeHoloprosencephaly (HPE) is a pathology of forebrain development characterized by high phenotypic and locus heterogeneity. Seventeen genes are known so far in HPE but the understanding of its genetic architecture remains to be refined. Here, we investigated the oligogenic nature of HPE resulting from accumulation of variants in different relevant genes.\n\nMethodsExome data from 29 patients diagnosed with HPE and 51 relatives from 26 unrelated families were analyzed. Standard variant classification approach was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis.\n\nResultsWe identified 232 rare deleterious variants in HPE patients representing 180 genes significantly associated with key pathways of forebrain development including Sonic Hedgehog (SHH) and Primary Cilia. Oligogenic events were observed in 10 families and involved novel HPE genes including recurrently mutated genes (FAT1, NDST1, COL2A1 and SCUBE2) and genes implicated in cilia function.\n\nConclusionsThis study reports novel HPE-relevant genes and reveals the existence of oligogenic cases resulting from several mutations in SHH-related genes. It also underlines that integrating clinical phenotyping in genetic studies will improve the identification of causal variants in rare disorders.

genetics↗