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.

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

“…MOPD type II is caused by mutations in PCNT encoding a key centrosomal protein. Meier-Gorlin syndrome (MGS) is caused by mutations in components of the prereplication and pre-initiation DNA replication complexes (ORC1, ORC4, ORC6, CDT1, CDC6, GMNN, CDC45), which license replication origins and mediate loading and functioning of the replication fork helicase (Bicknell et al 2011;Burrage et al 2015;Fenwick et al 2016). Although MMS is distinct from these four classic types of MPD syndromes, in this study we have presented genetic, transcriptomic, and proteomic evidence linking MMS and DONSON to other MPD syndromes, in particular, MGS.…”

Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

“…MGS occurs in an autosomal recessive manner due to germline mutations in one of the five genes encoding replication licensing factors ORC1, ORC4, ORC6, CDT1, and CDC6 [133–135,137,140]. Moreover, MGS can also be caused in an auto-somal dominant manner, as three patients harbor de novo mutations in GMNN which stabilizes its product geminin, the inhibitor of the licensing factor CDT1 [141]. Expression of geminin is regulated to occur in a restricted time from the beginning of S-phase to late mitosis to avoid re-licensing of origins [142,143].…”

HumanizedDrosophilamodel of the Meier-Gorlin syndrome reveals conserved and divergent features of the Orc6 protein

“…Meier-Gorlin Syndrome (MGS) is an autosomal recessive disorder that is also known as ear, patella, short stature syndrome and/or microtia, absent patella, micrognathia syndrome, highlighting the core clinical phenotypes (Gorlin et al 1975), (de Munnik et al 2012b), (de Munnik et al 2012a), (Bicknell et al 2011a). The genes affected by MGS mutations include many members of pre-replicative complex (pre-RC), such as ORC subunits (Orc1, Orc4, Orc6), Cdc6, Cdt1, CDC45, MCM5 as well as Geminin (Bicknell et al 2011a), (Bicknell et al 2011b), (Guernsey et al 2011), (Fenwick et al 2016), (Vetro et al 2017), (Burrage et al 2015), (McDaniel et al 2020) suggesting that the clinical phenotype is caused by defects in DNA replication initiation. As pre-RC complex is essential for DNA replication, the mutations in its components are expected to impair cell proliferation and to reduce growth.…”

“…and multiple developmental defects(de Munnik et al 2012b),(de Munnik et al 2012a),(Bicknell et al 2011a),(Kerzendorfer et al 2013). Mutations in a number of factors involved in DNA replication have been found to be causative for this disease(Bicknell et al 2011a),(Bicknell et al 2011b),(Guernsey et al 2011),(Fenwick et al 2016),(Vetro et al 2017),(Burrage et al 2015),(McDaniel et al 2020). Several mutations causing MGS were found in ORC subunits including Orc6(Bicknell et al 2011a),(Bicknell et al 2011b),(Guernsey et al 2011).…”