KIF21A – Congenital fibrosis of extraocular muscles

Congenital fibrosis of the extraocular muscles (CFEOM) is a non-progressive ophthalmoplegia syndrome characterized by bilateral ptosis and infraducted globes. Autosomal dominant mutations in the KIF21A gene underlie the classic CFEOM1 phenotype by disrupting kinesin autoinhibition. Over 25 unrelated probands have been reported with heterozygous KIF21A variants in multiple cohorts ([PMID:18332320]). The mode of inheritance is confirmed as autosomal dominant with high penetrance in most families.

Segregation analysis across at least 13 additional affected relatives supports variant pathogenicity. The variant spectrum is dominated by recurrent missense mutations in the third coiled-coil domain, most notably c.2860C>T (p.Arg954Trp), reported in sporadic and familial cases ([PMID:18332320]). Other missense alleles include c.84C>G (p.Cys28Trp) and c.2861G>A (p.Arg954Gln), each co-segregating with disease in pedigrees. No loss-of-function or splice variants have been convincingly associated with CFEOM, consistent with a gain-of-function mechanism.

Functional studies demonstrate that KIF21A disease alleles enhance motor activity and aberrantly recruit interacting partners. In vitro motility assays show increased kinesin processivity and plus-end dwell time on microtubules bearing CFEOM-causing β-tubulin mutations, confirming dysregulated transport ([PMID:38170592]). Cellular co-immunoprecipitation reveals enhanced membrane translocation of the Kank1 interactor by KIF21A p.Met947Thr and p.Arg954Trp variants, further supporting gain-of-function effects ([PMID:19559006]). Animal and yeast models of dominant KIF21A alleles recapitulate axon guidance defects and impaired neuronal development.

Some CFEOM1 pedigrees without KIF21A mutations indicate genetic heterogeneity, implicating additional FEOM loci ([PMID:11882252]). Moreover, rare CFEOM3 presentations have been linked to KIF21A alleles, underscoring phenotypic variability. No studies have refuted the core KIF21A–CFEOM1 association; instead, negative screens highlight locus heterogeneity rather than conflict.

Integration of genetic and experimental data yields a Strong clinical validity classification. The autosomal dominant KIF21A gain-of-function mechanism is well supported by segregation in >13 relatives and concordant functional assays. These findings inform molecular diagnosis, guide genetic counseling, and underpin future therapeutic strategies.

Key Take-home: KIF21A heterozygous gain-of-function variants cause autosomal dominant CFEOM1 with high penetrance and consistent functional impact, making KIF21A testing clinically imperative for early diagnosis and management.

References

• Archives of ophthalmology • 2008 • Novel and recurrent KIF21A mutations in congenital fibrosis of the extraocular muscles type 1 and 3 PMID:18332320
• Molecular biology of the cell • 2024 • Tubulin CFEOM mutations both inhibit or activate kinesin motor activity PMID:38170592
• Biochemical and biophysical research communications • 2009 • A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane PMID:19559006
• BMC genetics • 2002 • CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX PMID:11882252

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