Hot-spot KIF5A mutations cause familial ALS.

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Kinesin family member 5A (KIF5A) mutations cause hereditary spastic paraplegia and Charcot-Marie-Tooth disease.
• Dysregulation of cytoskeletal function and intracellular transport is implicated in amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

• To investigate the potential role of KIF5A mutations in the pathogenesis of familial amyotrophic lateral sclerosis (fALS).

Main Methods:

• Whole exome sequencing and rare variant analysis in 426 fALS patients and 6137 controls.
• Co-segregation analysis in affected families.
• Lymphoblastoid cell line analysis (RNA and mRNA sequencing) to assess molecular mechanisms.

Main Results:

• Enrichment of KIF5A splice-site mutations in fALS patients (P = 4.2 × 10-3).
• Identification of a C-terminal mutation hotspot associated with ALS.
• Demonstration of defective splicing and potential haploinsufficiency due to KIF5A mutations.
• Significant enrichment of a specific KIF5A C-terminal non-synonymous variant (rs113247976) in fALS patients (P = 1.28 × 10-7).

Conclusions:

• Mutations in a C-terminal hotspot of KIF5A can cause amyotrophic lateral sclerosis.
• These findings underscore the role of intracellular transport defects in ALS pathogenesis.