Open Access Open Badges Research article

Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1

Wai-Man Chan1, Caroline Andrews13, Laryssa Dragan4, Douglas Fredrick5, Linlea Armstrong6, Christopher Lyons7, Michael T Geraghty8, David G Hunter9, Ahmad Yazdani10, Elias I Traboulsi11, Jan WR Pott12, Nicholas J Gutowski1314, Sian Ellard14, Elizabeth Young14, Frank Hanisch15, Feray Koc16, Bruce Schnall17 and Elizabeth C Engle123*

Author Affiliations

1 Program in Genomics, Children's Hospital Boston, 300 Longwood Ave, Boston, MA, 02115, USA

2 Department of Neurology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA, 02115, USA

3 Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA

4 Department of Ophthalmology, Colorado Permanente Group, 10350 East Dakota Avenue, Denver, CO, 80231, USA

5 Department of Ophthalmology, University of California, San Francisco, 10 Koret Street, Room K335, San Francisco, CA 94143-0730, USA

6 Children's and Women's Health Centre of British Columbia, Provincial Medical Genetics Programme, 4500 Oak Street, Vancouver, BC, V6H 3N1, Canada

7 Department of Ophthalmology, University of British Columbia and British Columbia Children's Hospital, 4480 Oak Street, Vancouver, V6H 3V4 Vancouver, BC, Canada

8 Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, K1H 8L1, Canada

9 Department of Ophthalmology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA, 02115, USA

10 Khatam Eye Hospital, Mashad University of Medical Sciences, Shahid Ghareni Boulevard, Mashhad, Iran

11 Department of Pediatric Ophthalmology and The Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic Foundation, i32, 9500 Euclid Avenue Cleveland, OH, 44195, USA

12 Department of Ophthalmology, University Medical Center Groningen, University of Groningen, PO Box 30001, Groningen, 9700RB, The Netherlands

13 Department of Neurology, Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon, EX2 5DW, UK

14 Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK

15 Department of Neurology, Martin-Luther University Halle -Wittenberg, Ernst-Grube-Str. 40, D-06097 Halle/Saale, Germany

16 Strabismus Unit, SB Ulucanlar Eye Hospital, Kuzgun sok. 48/3 A, Ayranci, Ankara, Turkey

17 Department of Pediatric Ophthalmology, Wills Eye Hospital, 900 Walnut St Philadelphia, PA 19107, USA

For all author emails, please log on.

BMC Genetics 2007, 8:26  doi:10.1186/1471-2156-8-26

Published: 18 May 2007



Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in KIF21A. KIF21A encodes a kinesin motor involved in anterograde axonal transport, and the familial and de novo mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of KIF21A mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in KIF21A.


Sixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported de novo KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in KIF21A; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands.


Analysis of sixteen CFEOM1 probands revealed three novel KIF21A mutations and confirmed three reported mutations, bringing the total number of reported KIF21A mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.