Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome

JCI Insight. 2022 May 23;7(10):e155648. doi: 10.1172/jci.insight.155648.


The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.

Keywords: Cell Biology; Cell cycle; DNA repair; Genetic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosomal Proteins, Non-Histone
  • Congenital Microtia
  • DNA Replication / genetics
  • Growth Disorders
  • Humans
  • Mice
  • Micrognathism* / genetics
  • Minichromosome Maintenance Proteins / genetics
  • Patella / abnormalities
  • Saccharomyces cerevisiae*


  • Chromosomal Proteins, Non-Histone
  • GINS3 protein, human
  • Minichromosome Maintenance Proteins

Supplementary concepts

  • Meier-Gorlin syndrome

Grants and funding

NSERC grant to EIC