Abstract
Meier-Gorlin syndrome (MGORS) is a rare disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recessive mutations in ORC1, ORC4, ORC6, CDT1, CDC6, and CDC45, encoding members of the pre-replication (pre-RC) and pre-initiation (pre-IC) complexes, and heterozygous mutations in GMNN, a regulator of cell-cycle progression and DNA replication, have already been associated with this condition. We performed whole-exome sequencing (WES) in a patient with a clinical diagnosis of MGORS and identified biallelic variants in MCM5. This gene encodes a subunit of the replicative helicase complex, which represents a component of the pre-RC. Both variants, a missense substitution within a conserved domain critical for the helicase activity, and a single base deletion causing a frameshift and a premature stop codon, were predicted to be detrimental for the MCM5 function. Although variants of MCM5 have never been reported in specific human diseases, defect of this gene in zebrafish causes a phenotype of growth restriction overlapping the one associated with orc1 depletion. Complementation experiments in yeast showed that the plasmid carrying the missense variant was unable to rescue the lethal phenotype caused by mcm5 deletion. Moreover cell-cycle progression was delayed in patient’s cells, as already shown for mutations in the ORC1 gene. Altogether our findings support the role of MCM5 as a novel gene involved in MGORS, further emphasizing that this condition is caused by impaired DNA replication.
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Acknowledgements
AV benefits of a research position granted by the University of Pavia in the context of the strategic plan: Towards a governance model for international migration: an interdisciplinary and diachronic perspective (MIGRAT-IN-G). LS is supported by Telethon Italy Grant GGP13222, a grant from Fondazione CARIPARO, and University of Padova Grant CPDA123573/12; OZ is supported by Telethon Italy Grant GGP13060. The URLs for data presented herein are as follows: Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA, release ESP6500SI-V2 (http://evs.gs.washington.edu/EVS); ExAC (http://exac.broadinstitute.org); Integrative Genomics Viewer (IGV),http://www.broadinstitute.org/igv/Online Mendelian Inheritance in Man (OMIM), http://www.omim.org/ Phyre2 webserver http://www.sbg.bio.ic.ac.uk/phyre2/ Protein Data Bank (PDB), http://www.rcsb.org/pdb/home/home.do; and RefSeq, http://www.ncbi.nlm.nih.gov/RefSeq.
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Vetro, A., Savasta, S., Russo Raucci, A. et al. MCM5: a new actor in the link between DNA replication and Meier-Gorlin syndrome. Eur J Hum Genet 25, 646–650 (2017). https://doi.org/10.1038/ejhg.2017.5
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DOI: https://doi.org/10.1038/ejhg.2017.5
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