Mutation analysis of KIF21A in congenital fibrosis of the extraocular muscles (CFEOM) patients

Abstract

Abstract: : Purpose: CFEOM type 1 refers to a group of congenital eye movement disorders that is characterized by non progressive ophthalmoplegia affecting muscles in the oculomotor and trochlear nerve distribution. Individuals with the classic form of CFEOM are born with bilateral ptosis, infraducted eyes and impossibility to raise their eyes above midline. Neuropathologic findings suggest a primary defect in the development of the superior division of the oculomotor nerve (Engle et al. 1997). This phenotype is often inherited as an autosomal dominant trait. CFEOM1 maps to the FEOM1 locus on chromosome 12 and is the consequence of mutations in the KIF21A gene (Yamada et al. 2003). We analyzed 4 families and 1 sporadic case for potential genetic heterogeneity. Methods: Blood samples were collected from members of 4 families (Swiss and Turkish origin) and 1 sporadic case (Iranian origin). In families, haplotype was tested for linkage to the autosomal dominant CFEOM1 locus on chromosome 12. Linkage studies were conducted using 2 polymorphic DNA microsatellite markers, D12S331 and D12S1048. Mutation analysis was performed by PCR amplification and bidirectional direct sequencing. Results: Haplotype analysis was compatible with linkage to the CFEOM1 locus in all affected members. Mutation analysis revealed the classical mutation R954W in all affected cases, including the sporadic case, regardless of their ethnic origin. The 2860C/T base change was not observed in 100 individuals from various ethnic origins. Conclusions: As reported, the classical 2860C/T mutation represents a hotspot for mutation in various ethnic groups, including Swiss and Turkish patients. Sporadic cases are often due to neo–mutations as in our case. Mutation analysis is important, especially in sporadic cases, in order to correctly evaluate recurrence and transmission risks.

Keywords: mutations • extraocular muscles: development