Two novel CHN1 mutations in 2 families with Duane retraction syndrome.

OBJECTIVE: To determine the genetic cause of Duane retraction syndrome (DRS) in 2 families segregating DRS as a dominant trait.
METHODS: Members of 2 unrelated pedigrees were enrolled in a genetic study. Linkage analysis was performed on the CHN1 locus. Probands and family members were screened for CHN1 mutations.
RESULTS: The 6 affected individuals in the 2 pedigrees have DRS. Both pedigrees are consistent with linkage to the locus. Sequence analysis revealed 2 novel heterozygous missense CHN1 mutations, c.422C>T and c.754C>T, predicted to result in α2-chimaerin amino acid substitutions P141L and P252S, respectively.
CONCLUSIONS: Genetic analysis of 2 pedigrees revealed 2 novel DRS mutations, bringing the number of DRS pedigrees known to harbor CHN1 from 7 to 9. Both mutations alter residues that participate in intramolecular interactions that stabilize the inactive, closed conformation of α2-chimaerin and, thus, are predicted to result in its hyperactivation. Moreover, amino acid residue P252 was previously reported to be altered to a different residue in a previously reported DRS pedigree; thus, this is the first report of 2 CHN1 mutations altering the same residue, further supporting a gain-of-function etiology. CLINICAL RELEVANCE: Members of families segregating DRS as an autosomal dominant trait should be screened for mutations in the CHN1 gene, enhancing genetic counseling and permitting earlier diagnosis.