Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).
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.
Yamada
Koki
K
Department of Genetics, Children's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Chan
Wai-Man
WM
Andrews
Caroline
C
Bosley
Thomas M
TM
Sener
Emin C
EC
Zwaan
Johan T
JT
Mullaney
Paul B
PB
Oztürk
Banu T
BT
Akarsu
A Nurten
AN
Sabol
Louise J
LJ
Demer
Joseph L
JL
Sullivan
Timothy J
TJ
Gottlob
Irene
I
Roggenkäemper
Peter
P
Mackey
David A
DA
De Uzcategui
Clara E
CE
Uzcategui
Nicolas
N
Ben-Zeev
Bruria
B
Traboulsi
Elias I
EI
Magli
Adriano
A
de Berardinis
Teresa
T
Gagliardi
Vincenzo
V
Awasthi-Patney
Sudha
S
Vogel
Marlene C
MC
Rizzo
Joseph F
JF
Engle
Elizabeth C
EC
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
D018398:Homeodomain Proteins; C119023:KIF21A protein, human; D009419:Nerve Tissue Proteins; C491061:PHOX2A protein, human; D014157:Transcription Factors; D016547:Kinesins