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This summary describes the association between GMNN (HGNC:17493) and Meier-Gorlin syndrome (MONDO_0016817). Recent evidence from a multi‐patient study has identified three unrelated individuals with Meier-Gorlin syndrome who harbor de novo heterozygous mutations in the 5' region of GMNN (PMID:26637980). In these cases, the mutations affect the destruction box region of geminin, the protein encoded by GMNN, and are predicted to cause a gain‑of‑function effect. This mechanism appears to prolong the inhibition of DNA replication by stabilizing the protein, linking altered replication control with the clinical presentation of Meier-Gorlin syndrome.
Genetic evidence is based on reports of three affected probands carrying de novo variants, such as the truncating mutation c.16A>T (p.Lys6Ter) (PMID:26637980). These findings are notable given that Meier-Gorlin syndrome has traditionally been associated with autosomal‑recessive loss‑of‑function in other pre‑replication complex genes. Here, however, the autosomal dominant inheritance implied by the de novo events underscores a distinct mechanism for GMNN in the disease pathogenesis.
Functional studies provided in the report support the gain‑of‑function mechanism by demonstrating that disruption of the destruction box leads to increased protein stability and prolonged suppression of DNA replication. Though the cohort is small, the experimental findings are concordant with the expected cellular impact, thereby strengthening the biological plausibility of GMNN’s role in Meier‑Gorlin syndrome.
Despite the comprehensive functional evaluation, the genetic evidence remains limited by the small number of affected individuals and the absence of extended segregation analysis. Nonetheless, the converging genetic and functional data offer a compelling rationale for incorporating GMNN into diagnostic panels for Meier‑Gorlin syndrome.
Key take‑home sentence: Recognizing de novo gain‑of‑function mutations in GMNN is essential for accurate diagnosis and optimized management of patients presenting with Meier‑Gorlin syndrome phenotypes.
Gene–Disease AssociationLimitedThree affected probands with de novo heterozygous mutations (PMID:26637980) support the association, although the limited cohort size warrants a Limited classification. Genetic EvidenceLimitedThree unrelated cases with de novo mutations, including the truncating variant c.16A>T (p.Lys6Ter) (PMID:26637980), underpin the genetic evidence. Functional EvidenceModerateFunctional studies demonstrate that the mutations disrupt the destruction box of geminin, leading to increased protein stability and prolonged inhibition of DNA replication, consistent with a gain‑of‑function effect (PMID:26637980). |