title: Two novel CHN1 mutations in 2 families with Duane retraction syndrome.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Lily
authors.initials: L
authors.lastname: Zhu-Tam
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D020848:Chimerin 1 / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D004370:Duane Retraction Syndrome / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction
chemical_list: D020848:Chimerin 1