A Novel Variant of the KIF11 Gene, c.2922G>T, Is Associated with Microcephaly by Affecting RNA Splicing

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR) is a rare inherited disorder.
• Kinesin family member 11 (KIF11) mutations are implicated in microcephaly, but their precise role remains unclear.

Observation:

• Whole-exome sequencing identified a de novo heterozygous KIF11 mutation (c.2922G>T) in a patient with severe microcephaly.
• This variant was found to disrupt KIF11 pre-mRNA splicing, causing exon 20 deletion (c.2815_2922).

Findings:

• PBMC-derived pre-mRNA splicing assays and minigene experiments confirmed the splicing defect caused by the KIF11 variant.
• The exon 20 deletion results in a truncated KIF11 protein, suggesting a dominant-negative mechanism.

Implications:

• The identified KIF11 mutation provides a molecular explanation for MCLMR in this patient.
• Understanding this dominant-negative effect mechanism can inform future research into KIF11-related disorders and potential therapeutic strategies.