title: MCM5: a new actor in the link between DNA replication and Meier-Gorlin syndrome.
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.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Annalisa
authors.identifier: 0000-0003-2437-7526
authors.initials: A
authors.lastname: Vetro
authors.affiliation: Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Savasta
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Russo Raucci
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health University of Padova, Padova, Italy.|Laboratorio di Genetica Clinica ed Epidemiologica, Istituto di Ricerca Pediatrica, Città della Speranza, Padova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cerqua
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Geppo
authors.initials: G
authors.lastname: Sartori
authors.affiliation: enGenome s.r.l., Pavia, Italy.
authors.forename: Ivan
authors.identifier: 0000-0002-9781-2974
authors.initials: I
authors.lastname: Limongelli
authors.affiliation: Biochemistry Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.affiliation: Biochemistry Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maruelli
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Perucca
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Vergani
authors.affiliation: IGM-CNR Histochemistry and Cytometry Section, Department of Animal Biology, University of Pavia, Pavia, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Mazzini
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Lucia Anna
authors.initials: LA
authors.lastname: Stivala
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health University of Padova, Padova, Italy.|Laboratorio di Genetica Clinica ed Epidemiologica, Istituto di Ricerca Pediatrica, Città della Speranza, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Orsetta
authors.identifier: 0000-0002-1466-4559
authors.initials: O
authors.lastname: Zuffardi
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D018389:Codon, Nonsense; D065817:Congenital Microtia / Q000175:diagnosis / Q000235:genetics*; D004261:DNA Replication; D059472:Exome; D005816:Genetic Complementation Test; D006130:Growth Disorders / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008844:Micrognathism / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010329:Patella / Q000002:abnormalities*; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; C489423:MCM5 protein, human