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

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• The CMG helicase complex is crucial for DNA replication and cell survival.
• The GINS subcomplex is essential for CMG helicase activity.

Purpose of the Study:

• To investigate the role of GINS3 in Meier-Gorlin syndrome-like (MGS-like) phenotypes.
• To identify genetic variants in GINS3 associated with MGS-like features.

Main Methods:

• Identified hypomorphic GINS3 variants in patients with MGS-like phenotypes.
• Assessed the impact of GINS3 variants on cell proliferation, cell cycle progression, and protein stability.
• Utilized yeast models to study the functional consequences of GINS3 ortholog variants.
• Examined the effects of GINS3 variants on mouse embryonic development and fibroblast senescence.

Main Results:

• Identified novel GINS3 variants associated with MGS-like phenotypes in seven individuals from five families.
• MGS-associated GINS3 variants compromised cell proliferation and led to S phase arrest.
• These variants reduced GINS3 protein half-life, disrupted replisome interactions, and impaired DNA replication fork progression.
• Yeast models with equivalent PSF3 variants showed growth defects and reduced protein stability.
• Mouse embryos with homozygous GINS3 variants exhibited intrauterine growth retardation, failed to survive to birth, and displayed accelerated senescence in fibroblasts.

Conclusions:

• GINS3 variants are implicated in the pathogenesis of MGS.
• Hypomorphic GINS3 variants impair DNA replication, leading to compromised cell and organismal growth.
• This study expands the genetic basis of MGS and highlights the critical role of GINS3 in DNA replication and development.