CFEOM1 is the 'classic' form of CFEOM, and appears to be the most prevalent form of CFEOM. An individual with CFEOM1 has bilateral ptosis and bilateral ophthalmoplegia, with the primary position (resting position) of both eyes below the horizontal midline and the inability to raise either eye above the midline point. The horizontal movements of the eyes range from normal to severely limited. Residual eye movements can be very aberrant. The individual in the photograph has CFEOM1 and is holding her head back in order to see.
Given this definition of CFEOM1, most affected individuals are easily diagnosed and there is little variability in expression. CFEOM1 is not typically accompanied by other developmental abnormalities.
For a family to be classified as a 'CFEOM1 pedigree', all affected members of the family must have CFEOM1. In addition, the inheritance pattern in the family must be autosomal dominant and the penetrance must be complete.
In 1994, we mapped a gene for CFEOM1 to the centromere of chromosome 12. Over the subsequent years, we studied additional CFEOM1 families whose gene also mapped to this location. This was done using the technique of linkage analysis and involved the work of many of our collaborators.
The FEOM1 locus flanked the centromere of human chromosome 12. To identify the FEOM1 gene, Koki Yamada MD PhD, a postdoctoral fellow in the lab, screened transcripts within this region and identified mutations in KIF21A. We have subsequently identified KIF21A mutations in many additional families and in individuals with sporadic CFEOM11.
For more detailed information about the main CFEOM1 gene, click on KIF21A.
If you have CFEOM1, and would like KIF21A mutational analysis to be undertaken, please print off this Diagnostic testing sheet and take it to your ophthalmologist for completion. He/she can request the testing on your behalf and will need to draw 3-5cc of your blood to be placed into a purple capped (EDTA) vacutainer. A CLIA approved DNA Diagnostic Testing Laboratory based at Boston Children's Hospital will test your sample for the 'hotspot' KIF21A exons (exons 8, 20 and 21 of this 38 exon gene). If a mutation is identified results of the testing will be released to your physician who will convey the information to you. If a mutation is not identified, and you have signed this Informed Consent Form, the diagnostic laboratory will be permitted to pass an aliquot of your DNA over to the Engle lab for research analysis. We will screen your DNA sample for the remaining 35 KIF21A exons or candidate genes and, if anything is identified, it can then be confirmed by the CLIA lab.
You may either send your completed diagnostic testing sheet and blood sample directly to:
DNA Diagnostic Lab[CLIA #: 22D0001844]
Attention: Lab Control
300 Longwood Ave, Farley 7
Boston, MA 02115
Phone # 617.355.7582
Fax # 617.730.0338
or contact Caroline Andrews, who will describe the testing with you in more detail, and can organize processing of the sample. Also, please click on Diagnostic testing for individuals with CFEOM1, for answers to many questions regarding Diagnostic testing. The current cost for this mutation screening is approximately $600 and these charges should be covered by your health insurance provider. Please contact your insurance company for coverage information.
We have examined the brain and extraocular muscles of individuals with CFEOM1 using various techniques, including pathology and neuroimaging. Our findings are summarized in the schematic lateral view of the orbit below.
Normally, the oculomotor nucleus is in the midbrain of the brainstem, and its nerve (cranial nerve III) exits the brainstem and branches into a superior and inferior division. The superior division innervates the levator palpebrae (eyelid muscle) and the superior rectus (the eye muscle that pulls the eyeball upwards).
In individuals with CFEOM1, the superior division of cranial nerve III is absent or very small (normal nerves are yellow, and these absent axons are depicted as the red dotted lines). The motoneurons in the midbrain subnuclei whose axons make up the superior division of CN III are absent (depicted as absence of black outline of the tiny midbain CN III subnuclei). The levator palpebrae superioris and the superior rectus muscles are abnormal or absent. These muscles are normally innervated by the superior division of cranial nerve III (these muscles are depicted as blue rather than the normal brown). Dysfunction of the levator palpebrae would result in bilateral ptosis, and dysfunction of the superior rectus would result in the eyes fixed downward with an inability to elevate.
These data suggest that CFEOM1 results from a neurogenic (nerve) rather than a myopathic (muscle) cause.
With the identification of KIF21A mutations in individuals who have CFEOM1, we now hypothesize that this disorder is due to the inability of KIF21A to convey cargo necessary for the development of the CN III motor axons, neuromuscular junction or extraocular muscles. Our lab is now focused on identifying what the cargo and it it's interacting proteins may be, and this work is being undertaken by Koki Yamada, Maria Pia Rogines Velo-Sardi and Carlos Miranda.
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, last updated 12/15/2003 (entry number #135700).
Kinesins are family of molecular motor proteins found in many cell types. In neurons, they are responsible for anterograde axonal transport of organelles, protein complexes, and mitochondria from the neuron cell body down the axon to the synapse. These kinesin molecules have a motor at one end that interacts with tubulin and 'walks' down the microtubule tract within an axon. At the other end, the kinesin molecules have a cargo loading area, where they interact with the cargo they transport. In the middle of the molecule is the flexible stalk, connecting the motor to the cargo regions. Different kinesin molecules have different cargo loading regions, specific for the cargo they are designed to transport.
In 2003 we identified the developmental kinesin KIF21A as the CFEOM1 disease gene. Below is the predicted structure of KIF21A.
Predicted KIF21A protein structure with the domains indicated.
The motor domain is blue, the cargo loading region, made up of seven WD40 repeats in the tail, is green, and the stalk is grey. Within the stalk are three coiled-coil regions indicated in yellow. Two alternatively spliced regions in the stalk are white. The locations of pathogenic (disease causing) mutations are shown in color as red triangles. Five are located in the third coiled-coil region and one is at the end of the motor domain. Non-pathogenic polymorphisms that we have identified are shown as blue dots, and are in the stalk outside of a coiled-coil region.
In human fetal tissue, a Northern blot analysis shows that KIF21A mRNA is abundant in the brain with lower levels in liver and kidney.
The picture below shows RT-PCR analysis of this protein's expression (undertaken using northern-blot hybridization) and revealed abundant expression in most of the central nervous system, with primary expression in the brain and lower levels in heart, skeletal muscle and kidney.
RT-PCR analysis of KIF21A expression in human adult tissue
We believe that CFEOM1 is probably caused by the inability of mutated KIF21A to deliver a cargo that is necessary for the development of oculomotor axons, extraocular muscles and the neuromuscular junction. We are currently working to identify what the cargo and its interacting proteins are and hope to gain further understanding of the role of this kinesin in cranial nerve and extraocular muscle development.
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, creation date 11/12/2003 (entry number *608283). Home page: http://www3.ncbi.nlm.nih.gov/Omim/.
Goldstein LS. Molecular motors: from one motor many tails to one motor many tales. Trends Cell Biol. 2001 Dec;11(12):477-82.
Yamada K, Andrews C, Chan WM, McKeown CA, Magli A, de Berardinis T, Loewenstein A, Lazar M, O'Keefe M, Letson R, London A, Ruttum M, Matsumoto N, Saito N, Morris L, Del Monte M, Johnson RH, Uyama E, Houtman WA, de Vries B, Carlow TJ, Hart BL, Krawiecki N, Shoffner J, Vogel MC, Katowitz J, Goldstein SM, Levin AV, Sener EC, Ozturk BT, Akarsu AN, Brodsky MC, Hanisch F, Cruse RP, Zubcov AA, Robb RM, Roggenkaemper P, Gottlob I, Kowal L, Battu R, Traboulsi EI, Franceschini P, Newlin A, Demer JL, Engle EC. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet. 2003 Dec;35(4):318-21. Epub 2003 Nov 02.
Yamada K, Chan WM, Andrews C, Bosley TM, Sener EC, Zwaan JT, Mullaney PB, Ozturk BT, Akarsu AN, Sabol LJ, Demer JL, Sullivan TJ, Gottlob I, Roggenkaemper P, Mackey DA, De Uzcategui CE, Uzcategui N, Ben-Zeev B, Traboulsi EI, Magli A, de Berardinis T, Gagliardi V, Awasthi-Patney S, Vogel MC, Rizzo JF 3rd, Engle EC. Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3). Invest Ophthalmol Vis Sci. 2004 Jul;45(7):2218-23. http://www.iovs.org/cgi/content/full/45/7/2218