title: Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).
abstract: OBJECTIVE
  Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3.
  
  
  METHODS
  All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A.
  
  
  RESULTS
  Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A.
  
  
  CONCLUSIONS
  The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.
authors.affiliation: Department of Genetics, Children's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Koki
authors.initials: K
authors.lastname: Yamada
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bosley
authors.forename: Emin C
authors.initials: EC
authors.lastname: Sener
authors.forename: Johan T
authors.initials: JT
authors.lastname: Zwaan
authors.forename: Paul B
authors.initials: PB
authors.lastname: Mullaney
authors.forename: Banu T
authors.initials: BT
authors.lastname: Oztürk
authors.forename: A Nurten
authors.initials: AN
authors.lastname: Akarsu
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Sabol
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Demer
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sullivan
authors.forename: Irene
authors.initials: I
authors.lastname: Gottlob
authors.forename: Peter
authors.initials: P
authors.lastname: Roggenkäemper
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Clara E
authors.initials: CE
authors.lastname: De Uzcategui
authors.forename: Nicolas
authors.initials: N
authors.lastname: Uzcategui
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.forename: Elias I
authors.initials: EI
authors.lastname: Traboulsi
authors.forename: Adriano
authors.initials: A
authors.lastname: Magli
authors.forename: Teresa
authors.initials: T
authors.lastname: de Berardinis
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Gagliardi
authors.forename: Sudha
authors.initials: S
authors.lastname: Awasthi-Patney
authors.forename: Marlene C
authors.initials: MC
authors.lastname: Vogel
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Rizzo
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D005355:Fibrosis; D008040:Genetic Linkage; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009801:Oculomotor Muscles / Q000473:pathology*; D009886:Ophthalmoplegia / Q000151:congenital* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C119023:KIF21A protein, human; D009419:Nerve Tissue Proteins; C491061:PHOX2A protein, human; D014157:Transcription Factors; D016547:Kinesins