De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome

Lindsay C. Burrage, Wu-Lin Charng, Mohammad K. Eldomery, Jason R. Willer, Erica E. Davis, Dorien Lugtenberg, Wenmiao Zhu, Magalie S. Leduc, Zeynep C. Akdemir, Mahshid Azamian, Gladys Zapata, Patricia P. Hernandez, Jeroen Schoots, Sonja A. de Munnik, Ronald Roepman, Jillian N. Pearring, Shalini Jhangiani, Nicholas Katsanis, Lisenka E.L.M. Vissers, Han G. Brunner, Arthur L. Beaudet, Jill A. Rosenfeld, Donna M. Muzny, Richard A. Gibbs, Christine M. Eng, Fan Xia, Seema R. Lalani, James R. Lupski, Ernie M.H.F. Bongers, Yaping Yang

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.