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

Publication ,  Journal Article
Burrage, LC; Charng, W-L; Eldomery, MK; Willer, JR; Davis, EE; Lugtenberg, D; Zhu, W; Leduc, MS; Akdemir, ZC; Azamian, M; Zapata, G; Muzny, DM ...
Published in: Am J Hum Genet
December 3, 2015

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

December 3, 2015

Volume

97

Issue

6

Start / End Page

904 / 913

Location

United States

Related Subject Headings

  • Sequence Alignment
  • RNA Splicing
  • Proteolysis
  • Protein Stability
  • Pedigree
  • Patella
  • Mutation
  • Molecular Sequence Data
  • Micrognathism
  • Male
 

Citation

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Burrage, L. C., Charng, W.-L., Eldomery, M. K., Willer, J. R., Davis, E. E., Lugtenberg, D., … Yang, Y. (2015). De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Am J Hum Genet, 97(6), 904–913. https://doi.org/10.1016/j.ajhg.2015.11.006
Burrage, Lindsay C., Wu-Lin Charng, Mohammad K. Eldomery, Jason R. Willer, Erica E. Davis, Dorien Lugtenberg, Wenmiao Zhu, et al. “De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.Am J Hum Genet 97, no. 6 (December 3, 2015): 904–13. https://doi.org/10.1016/j.ajhg.2015.11.006.
Burrage LC, Charng W-L, Eldomery MK, Willer JR, Davis EE, Lugtenberg D, et al. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Am J Hum Genet. 2015 Dec 3;97(6):904–13.
Burrage, Lindsay C., et al. “De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.Am J Hum Genet, vol. 97, no. 6, Dec. 2015, pp. 904–13. Pubmed, doi:10.1016/j.ajhg.2015.11.006.
Burrage 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. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Am J Hum Genet. 2015 Dec 3;97(6):904–913.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

December 3, 2015

Volume

97

Issue

6

Start / End Page

904 / 913

Location

United States

Related Subject Headings

  • Sequence Alignment
  • RNA Splicing
  • Proteolysis
  • Protein Stability
  • Pedigree
  • Patella
  • Mutation
  • Molecular Sequence Data
  • Micrognathism
  • Male