title: De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Burrage
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Eldomery
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Willer
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.affiliation: Exome Laboratory, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Wenmiao
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Magalie S
authors.initials: MS
authors.lastname: Leduc
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zeynep C
authors.initials: ZC
authors.lastname: Akdemir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mahshid
authors.initials: M
authors.lastname: Azamian
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Zapata
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Hernandez
authors.affiliation: Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schoots
authors.affiliation: Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Sonja A
authors.initials: SA
authors.lastname: de Munnik
authors.affiliation: Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Jillian N
authors.initials: JN
authors.lastname: Pearring
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Exome Laboratory, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Exome Laboratory, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Exome Laboratory, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Human Genetics, Radboud university medical center, P.O. Box 9101, 6500 HB, Nijmegen, the Netherlands. Electronic address: ernie.bongers@radboudumc.nl.
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Exome Laboratory, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA. Electronic address: yapingy@bcm.edu.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D002675:Child, Preschool; D065817:Congenital Microtia / Q000235:genetics* / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005091:Exons; D005260:Female; D064248:Geminin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005799:Genes, Dominant; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008844:Micrognathism / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010329:Patella / Q000002:abnormalities* / Q000378:metabolism; D010375:Pedigree; D055550:Protein Stability; D059748:Proteolysis; D012326:RNA Splicing; D016415:Sequence Alignment
chemical_list: C577995:GMNN protein, human; D064248:Geminin