title: Expansion of the CHN1 strabismus phenotype.
abstract: OBJECTIVE
  Hyperactivating CHN1 mutations have been described in individuals with Duane retraction syndrome with or without vertical gaze abnormalities. This was a study of five family members with distinctive ocular dysmotility patterns that co-segregated with a novel hyperactivating CHN1 mutation.
  
  
  METHODS
  Participating members of a family segregating pleomorphic incomitant strabismus underwent ophthalmic examinations, and several underwent high-resolution magnetic resonance imaging (MRI) of the orbits and brain stem. Participant DNA was extracted and amplified for haplotype analysis encompassing the CHN1 region on chromosome 2q31.1, and mutation analysis of the CHN1 gene, which encodes the Rac-GAP signaling protein α2-chimaerin. In vitro functional studies of the co-inherited mutation were performed, including a Rac-GTP activation assay, quantification of α2-chimaerin translocation, and co-immunoprecipitation.
  
  
  RESULTS
  All five clinically affected family members exhibited monocular or binocular supraduction deficits, three in the absence of Duane retraction syndrome. MRI in four affected individuals demonstrated small or absent abducens nerves in all four, small oculomotor nerve in one, and small optic nerves in three. Superior oblique muscle volume was also decreased in three of the individuals, supporting trochlear nerve hypoplasia. Strabismus segregated with the CHN1 locus and affected individuals harbored a c.443A>T CHN1 mutation (p.Y148F). In vitro, this novel mutation behaved similarly to previously reported CHN1 mutations underlying familial Duane syndrome, hyperactivating α2-chimaerin by enhancing its dimerization and membrane association and lowering total intracellular Rac-GTP.
  
  
  CONCLUSIONS
  Analysis of the current pedigree expands the phenotypic spectrum of hyperactivating CHN1 mutations to include vertical strabismus and supraduction deficits in the absence of Duane retraction syndrome.
authors.affiliation: Departments of Neurology, Children’s Hospital Boston, Boston, Massachusetts 02115, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Demer
authors.forename: Sherin
authors.initials: S
authors.lastname: Shaaban
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Christiansen
authors.forename: David G
authors.initials: DG
authors.lastname: Hunter
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D000010:Abducens Nerve / Q000002:abnormalities; D019943:Amino Acid Substitution; D020848:Chimerin 1 / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003389:Cranial Nerve Diseases / Q000175:diagnosis; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D008040:Genetic Linkage; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D009882:Ophthalmic Nerve / Q000002:abnormalities; D009900:Optic Nerve / Q000002:abnormalities; D010375:Pedigree; D010641:Phenotype; D013285:Strabismus / Q000235:genetics*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020848:Chimerin 1; D020744:rac GTP-Binding Proteins