KIF21A-associated peripheral neuropathy defined by impaired binding with TUBB3

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• KIF21A mutations are linked to congenital fibrosis of the extraocular muscles (CFEOM) due to disrupted intramolecular interactions.
• The KIF21A protein is a kinesin motor essential for neuronal development and function.

Purpose of the Study:

• To characterize a novel de novo KIF21A variant and its associated phenotype.
• To investigate the molecular mechanism underlying the KIF21A variant's effects on protein structure and interactions.

Main Methods:

• Genetic sequencing to identify the KIF21A variant.
• Protein modeling to predict structural changes.
• Co-immunoprecipitation assays to assess KIF21A-TUBB3 binding.

Main Results:

• A novel heterozygous de novo missense variant, KIF21A p.Leu664Pro, was identified in a patient with peripheral neuropathy, corpus callosum hypoplasia, and strabismus.
• Protein modeling indicated significant structural alterations and predicted impaired binding with TUBB3.
• In vitro experiments confirmed reduced KIF21A p.Leu664Pro binding to TUBB3.

Conclusions:

• The KIF21A p.Leu664Pro variant defines a new phenotype including progressive peripheral neuropathy, brain anomalies, developmental delay, and strabismus.
• Disruption of the KIF21A-TUBB3 interaction is a potential mechanism for this novel KIF21A-related disorder.