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

TitleDe Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.
Publication TypeJournal Article
Year of Publication2015
AuthorsBurrage, LC, Charng, W-L, Eldomery, MK, Willer, JR, Davis, EE, Lugtenberg, D, Zhu, W, Leduc, MS, Akdemir, ZC, Azamian, M, Zapata, G, Hernandez, PP, Schoots, J, de Munnik, SA, Roepman, R, Pearring, JN, Jhangiani, S, Katsanis, N, Vissers, LELM, Brunner, HG, Beaudet, AL, Rosenfeld, JA, Muzny, DM, Gibbs, RA, Eng, CM, Xia, F, Lalani, SR, Lupski, JR, Bongers, EMHF, Yang, Y
JournalAm J Hum Genet
Date Published2015 Dec 03
KeywordsAdolescent, Amino Acid Sequence, Base Sequence, Cell Cycle, Child, Preschool, Congenital Microtia, Dwarfism, Exons, Female, Geminin, Gene Expression, Genes, Dominant, Growth Disorders, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Inheritance Patterns, Male, Micrognathism, Molecular Sequence Data, Mutation, Patella, Pedigree, Protein Stability, Proteolysis, RNA Splicing, Sequence Alignment

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.

Alternate JournalAm J Hum Genet
PubMed ID26637980
PubMed Central IDPMC4678788
Grant ListK12 HD001399 / HD / NICHD NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54HD061221 / HD / NICHD NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
U54 HD061221 / HD / NICHD NIH HHS / United States
P50 DK096415 / DK / NIDDK NIH HHS / United States
T32 GM07526 / GM / NIGMS NIH HHS / United States
K99 EY025732 / EY / NEI NIH HHS / United States

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