Through genetic and neurodevelopmental studies, we have discovered that complex strabismus syndromes can be sensitive indicators of human genetic errors in axon growth and guidance. These include horizontal gaze palsy with progressive scoliosis, Duane syndrome, and CFEOM1 that result from mutations in ROBO3, CHN1, and KIF21A, respectively. During the previous grant cycle, we identified the CFEOM3 gene to be TUBB3, which encodes the neuron-specific β-tubulin isotype III, and defined this as a fourth disorder of axon guidance. We found that an allelic series of heterozygous missense mutations in this gene cause a spectrum of human nervous system disorders that result from aberrant axon guidance and maintenance. While each mutation causes CFEOM3, some also result in axonal neuropathy, facial paralysis, intellectual and behavioral impairments, among other findings. Conventional neuroimaging highlighted a spectrum of abnormalities including hypoplasia of oculomotor nerves, and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in mouse model revealed axon guidance defects without evidence of cortical cell migration abnormalities. Several of the disease-associated TUBB3 substitutions reside at putative kinesin interaction sites on β-tubulin, and we found that microtubules from knock-in mice had decreased interactions with the CFEOM1 gene product, Kif21a. We now propose two translational Aims to continue our studies of CFEOM and the TUBB3 syndromes. We will further determine and define the TUBB3 phenotypes, including through the use of diffusion spectrum imaging to visualize white matter tracts in living participants and in ex vivo mouse models. Second, given the success of our genetic approach to identify disorders of axon guidance, we will continue our ongoing ascertainment and genetic analysis of CFEOM in order to identify additional disease genes. Following the completion of these Aims, we will have phenotypically defined one of the few known genetic disorders of axon guidance and potentially identified additional disorders, thus aiding our understanding of human neurological diseases.
For neurons to properly signal to each other and to muscle, their long processes, called axons, must form precise and predictable connections during development. We have defined an allelic series of mutations in a gene that alter the function of the microtubule cytoskeleton, perturb axon guidance and survival, and result in significant ophthalmological and neurological dysfunction. This proposal aims to define the clinical aspects of these disorders, and to identify and define new disorders, in order to both improve patient care and our overall understanding of axon connectivity in human disease.
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