The GMNN gene is located on chromosome 6 at 6p22.3 and encodes the geminin DNA replication inhibitor, a ubiquitously expressed protein that inhibits DNA replication by binding the DNA replication factor CDT1 and preventing the incorporation of mini-chromosome maintenance proteins into the pre-replication complex. The GMNN gene was first reported in relation to AD Meier-Gorlin Syndrome 6 (MGS6) in 2015 (Burrage et al. 2015, PMID:26637980). Meier-Gorlin syndrome is characterized by a clinical triad of symptoms: short stature, microtia, and small or absent patellae. In addition to the MGS triad, some individuals with MGS6 have marked lumbar lordosis, failure to thrive and developmental delay and/or cognitive impairment. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Three unique de novo variants reported in three individuals with Meier-Gorlin syndrome 6 from one publication (PMID:26637980) are included in this curation. These variants include one missense, one frameshift, and one nonsense, all in the first coding exon and predicted to result in a stable truncated protein starting at Met28. The mechanism of disease is unknown but suggestive of heterozygous gain-of-function/dominant negative. Supporting experimental evidence includes protein interaction data and a cell culture model. Several genes involved in DNA replication initiation have been associated with Meier-Gorlin syndrome. The GMNN protein is an inhibitor of the DNA replication initiation complex through direct CDT1 binding. The gene-disease relationship for CDT1 with Meier-Gorlin syndrome 4 has been curated and classified as definitive for (Caillat et al. 2012, PMID:22918581). Studies on an HCT116 cell culture model expressing an N-terminus truncated GMNN protein with an interrupted destruction box sequence (met-28 start) showed increased protein stability,reduced chromatin loading of MCM complex proteins, inhibited DNA replication, and impaired cell growth (Yoshida et al. 2004, PMID:14712211). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date Dec 4th, 2024 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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