Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.

Area of Science:

• Genetics
• Molecular Biology
• Genomic Instability

Background:

• Bloom syndrome is linked to BLM mutations, causing growth deficiency, cancer predisposition, and elevated sister chromatid exchanges (SCEs).
• The BLM helicase functions with the BTRR complex in DNA repair pathways, including Holliday junction dissolution.

Purpose of the Study:

• To identify genetic causes of prenatal-onset growth restriction and microcephaly associated with elevated SCEs.
• To investigate the role of the BLM-associated BTRR complex in human genetic disorders.

Main Methods:

• Whole-exome sequencing and cytogenetic analysis were performed on affected individuals.
• Cellular assays were used to assess topoisomerase III alpha (TopIIIα) levels and SCE rates.
• Functional studies examined the role of TOP3A and RMI1 in DNA repair and mitochondrial function.

Main Results:

• Biallelic mutations in TOP3A were identified in ten individuals with prenatal growth restriction and microcephaly.
• A homozygous variant in RMI1 was found in two individuals with microcephalic dwarfism.
• TOP3A mutations led to reduced TopIIIα levels, increased SCEs, chromosome segregation defects, and genome instability.
• Mitochondrial dysfunction was observed in individuals with TOP3A mutations, suggesting a role in mitochondrial DNA decatenation.

Conclusions:

• Mutations in TOP3A are a novel cause of prenatal-onset short stature with increased SCEs, distinct from but mechanistically related to Bloom syndrome.
• The BTRR complex, particularly TopIIIα's decatenation activity, is crucial for preventing genome instability and is implicated in the pathogenesis of these growth disorders.