KIF1C – Spastic Ataxia 2

KIF1C‐related spastic ataxia 2 is an autosomal recessive neurodegenerative disorder characterized by progressive lower limb spasticity and cerebellar dysfunction, reflecting pyramidal tract and cerebellar involvement. Affected individuals present in childhood with spastic paraparesis and ataxia, often accompanied by mild proximal weakness. Magnetic resonance imaging may show cerebellar atrophy. The inheritance pattern and early onset guide genetic testing towards recessive kinesin motor gene defects, including KIF1C.

In two consanguineous families of Palestinian and Moroccan ancestry, autozygosity mapping and classical linkage localized the disease locus to chromosome 17, overlapping SPAX2 (spastic ataxia type 2) ([PMID:24319291]). Whole‐exome sequencing identified two homozygous KIF1C mutations absent from population controls: a nonsense variant c.2191C>T (p.Arg731Ter) and a missense variant c.505C>T (p.Arg169Trp) that affect the motor domain and abolish protein expression or function ([PMID:24319291]).

Variant spectrum across studies includes loss‐of‐function alleles (nonsense and frameshift) and missense changes impacting ATPase and microtubule binding domains. The prototypical c.2191C>T (p.Arg731Ter) variant causes complete absence of KIF1C protein in patient fibroblasts. No recurrent or founder alleles beyond these two kindreds have been reported.

Segregation analysis confirmed co‐segregation of homozygous KIF1C variants with disease in four affected individuals across two families, with zero instances in unaffected relatives ([PMID:24319291]). This underscores a clear recessive inheritance pattern.

Functional studies demonstrate loss of KIF1C impairs motor activity and intracellular trafficking. Patient fibroblasts lack detectable KIF1C protein, and expression of mutant alleles fails to rescue localization to neurite projections ([PMID:24319291]). Further, KIF1C is shown to transport exon junction complex–bound mRNA along neuronal processes, and mutant protein mislocalizes EJC components to the pericentrosomal region in SH‐SY5Y neurons ([PMID:36316088]).

Together, genetic and experimental data establish a moderate level of clinical validity for the association between KIF1C and spastic ataxia 2. Additional studies could expand variant spectra and clarify genotype–phenotype correlations. Key take-home: biallelic loss‐of‐function or missense variants in KIF1C cause autosomal recessive spastic ataxia 2, supporting its inclusion in diagnostic gene panels for HSP and cerebellar ataxia.

References

• Journal of medical genetics • 2014 • KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction. PMID:24319291
• Neurology • 2014 • Motor protein mutations cause a new form of hereditary spastic paraplegia. PMID:24808017
• RNA (New York, N.Y.) • 2022 • The kinesin motor KIF1C is a putative transporter of the exon junction complex in neuronal cells. PMID:36316088

Evidence Based Scoring (AI generated)