Several human syndromes are caused by mutations in genes coding for proteins that regulate the completion and fidelity of DNA replication: Seckel syndrome, Bloom syndrome, Van Esch-O’Driscoll disease, IMAGe syndrome... One of the common feature of these syndromes is a growth defect, often observed in utero and called primary dwarfism.

Meier-Gorlin Syndrome (MGS) is a rare autosomal recessive disorder combining short stature with poor growth with a variable number of developmental abnormalities such as small ears and absent patella (ORPHA: 2554). Since 2011, studies have shown that pathological variants in genes encoding ORC (origin of replication recognition complex) subunits, CDT1, GEMININ, CDC45, DONSON, GINS and MCM complex subunits are involved in the etiology of the disease (see Bicknell et al., 2011 & Nielsen-Dandoroff et al., 2023). The mutations causing the most severe phenotype alter the function of the gene encoding the ORC1 subunit of the ORC complex, and the most recurrent of them corresponds to the substitution of arginine 105 by glutamine in the BAH (for "bromo-adjacent homology") domain, a highly conserved functional domain linked with chromatin-binding activity (see Bicknell et al., 2011 & Kuo et al., 2022 & Nielsen-Dandoroff et al., 2023).

Our team seeks to understand :
- What are the molecular and cellular consequences of MGS mutations in human cells?
- Are there other, non-canonical, functions associated with replication initiation factors?
- What are the biological functions of replication initiation factors during early embryogenesis?

To answer these questions, the team has several cell models derived from patient samples, such as fibroblasts, stem cells and lymphocytes, as well as a mouse model of the disease.

Ongoing projects are supported by Agence Nationale de la Recherche, Fondation Maladies Rares, INSERM, CNRS, University Paris Cité and the 'Filière Santé Maladies Rares de l’os, du calcium et du cartilage' OSCAR.