Our long-term research goal is to understand oculomotor development and the pathogenesis of congenital ocular motor diseases. We address this goal through genetic and neurodevelopmental studies of complex congenital eye movement disorders and their mutated genes. We hypothesize that these disorders result from errors in cranial motoneuron development and axonal targeting within the brainstem and orbit/This is supported by our clinical, magnetic resonance imaging (MRI) and neuropathology studies, and by our identification of KIF21A, PHOX2A, HOXA1, SALL4, and ROBO3 as the genes mutated in CFEOM1, CFEOM2, HOXA1-related syndromes, DRRS, and HGPPS, respectively. These findings have led us to reclassifythese syndromes as the 'congenital cranial dysinnervation disorders'(CCDDs). As part of this grant's previous cycle, we defined the MRI characteristics of a subset of CCDDs, identified and characterized a kinesin, KIF21A, as the CFEOM1 gene, generated a knock-in mouse model that recapitulates the CFEOM phenotype, and identified putative KIF21A binding partners through yeast two hybrid analysis. By identifying the FEOM1 gene and defining the neuropathology of CFEOM1 in humans, we have identified the first kinesin to be directly associated with a neurodevelopmental disorder and one with an apparently restricted clinical phenotype. In this renewal, we proposeto more precisely determine the neuroanatomic, cellular, and molecular basis of CFEOM1 and continue to obtain and analyze MR images of the brain and orbit in patients with genetically defined CCDDs. We propose the following Aims.
Aim 1 : Define the anatomic and functional basis of the CCDDs by high resolution MR imaging of the brain and orbit in individuals with genetically defined CCDDs.
Aim 2 : Define the spatial and temporal developmental expression profile of KIF21A in mouse and human.
Aim 3 : Define the cellular consequences of the R954W amino acid substitution on the developing and mature ocular motor axis in mice.
Aim 4 : Identify KIF21A protein binding partners.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Central Visual Processing Study Section (CVP)
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Chin, Hemin R
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Children's Hospital Boston
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Cheng, Long; Desai, Jigar; Miranda, Carlos J et al. (2014) Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling. Neuron 82:334-49
Desai, Jigar; Velo, Marie Pia Rogines; Yamada, Koki et al. (2012) Spatiotemporal expression pattern of KIF21A during normal embryonic development and in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Gene Expr Patterns 12:180-8
Miyake, Noriko; Demer, Joseph L; Shaaban, Sherin et al. (2011) Expansion of the CHN1 strabismus phenotype. Invest Ophthalmol Vis Sci 52:6321-8
Oystreck, Darren T; Engle, Elizabeth C; Bosley, Thomas M (2011) Recent progress in understanding congenital cranial dysinnervation disorders. J Neuroophthalmol 31:69-77
Tischfield, Max A; Engle, Elizabeth C (2010) Distinct alpha- and beta-tubulin isotypes are required for the positioning, differentiation and survival of neurons: new support for the 'multi-tubulin' hypothesis. Biosci Rep 30:319-30
Tischfield, Max A; Baris, Hagit N; Wu, Chen et al. (2010) Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 140:74-87
Yang, Xian; Yamada, Koki; Katz, Bradley et al. (2010) KIF21A mutations in two Chinese families with congenital fibrosis of the extraocular muscles (CFEOM). Mol Vis 16:2062-70
Engle, Elizabeth C (2010) Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol 2:a001784
Demer, Joseph L; Clark, Robert A; Tischfield, Max A et al. (2010) Evidence of an asymmetrical endophenotype in congenital fibrosis of extraocular muscles type 3 resulting from TUBB3 mutations. Invest Ophthalmol Vis Sci 51:4600-11
Flaherty, Maree P; Balachandran, Chandra; Jamieson, Robyn et al. (2009) Congenital fibrosis of the extraocular muscles type 1, distinctive conjunctival changes and intrapapillary disc colobomata. Ophthalmic Genet 30:91-5

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