Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• Aneuploidy, abnormal chromosome numbers, is a primary cause of miscarriage, congenital birth defects, and cancer.
• The genetic underpinnings of aneuploidy are not well understood, limiting therapeutic and diagnostic strategies.

Purpose of the Study:

• To investigate the genetic basis of constitutional mosaic aneuploidy.
• To identify novel genes and molecular mechanisms contributing to aneuploidy.

Main Methods:

• Exome sequencing was performed on patients diagnosed with constitutional mosaic aneuploidy.
• Functional studies were conducted to assess the role of identified gene mutations in splicing and chromosome segregation.

Main Results:

• Biallelic truncating mutations in CENATAC (CCDC84) were identified as a cause of aneuploidy.
• CENATAC is a novel component of the U12-dependent minor spliceosome, essential for splicing specific AT-AN minor introns.
• CENATAC deficiency leads to intron retention in key regulatory genes and causes chromosome segregation errors.

Conclusions:

• Defects in the minor spliceosome, specifically involving CENATAC, can lead to constitutional aneuploidy in humans.
• This discovery provides a new genetic link between splicing defects and aneuploidy, opening avenues for research into related diseases.