The goal of this proposal is to understand the genetic and functional anatomical basis underlying autosomal recessive horizontal gaze palsy with progressive scoliosis (HGPPS; OMIM 607313), the disease locus of which we recently mapped to 11q23-25. This condition is characterized by a complete absence of conjugate horizontal eye movement at birth, with a delayed development of progressive scoliosis during infancy and childhood. Absent horizontal gaze likely results from maldevelopment of the abducens nuclei, involving both abducens moto- and inter-neurons. The recruitment of additional HGPPS patients has enabled the confirmation as well as narrowing of the candidate region in six ethnically diverse inbred families. Continuing effort to identify new patients may further narrow the region.
The specific aims for this proposal are: 1) To test the hypothesis that the HGPPS gene is a novel patterning gene. Already underway, candidate gene sequencing will be prioritized based on neuronal expression pattern, putative function in neurodevelopment, and orthologous genes in mice and other organisms. 2) To test the hypothesis that maldevelopment of the abducens nucleus is the anatomical basis of HGPPS. Innovative high-resolution conventional, diffusion tensor, and functional MRI studies will be performed in normal and genetically characterized patients to define the functional anatomical basis of horizontal gaze dysfunction localizing to the brainstem, which has not been well visualized. 3) To test the hypothesis that the HGPPS gene is important in the normal development of the abducens nucleus and other brainstem structures. We will examine expression of the HGPPS gene in embryonic brain tissue from human and mouse (wildtype and developmental mutants) to study its role in the cascade of genetically programmed signaling pathways mediating neurogenesis. Neuroimaging techniques that we develop will be applicable to the study of other brainstem structures important in oculomotor control. Understanding the anatomical and molecular basis of HGPPS will provide insight into the genetically programmed neurodevelopment of the conjugate horizontal gaze center and other cranial nuclei in the brainstem. ? ?
|Rudnik-Schöneborn, Sabine; Senderek, Jan; Jen, Joanna C et al. (2013) Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology 80:438-46|
|Wan, Jijun; Yourshaw, Michael; Mamsa, Hafsa et al. (2012) Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet 44:704-8|
|Vespa, P M; McArthur, D L; Xu, Y et al. (2010) Nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy. Neurology 75:792-8|
|Jen, Joanna C (2008) Effects of failure of development of crossing brainstem pathways on ocular motor control. Prog Brain Res 171:137-41|
|Salamon, N; Sicotte, N; Drain, A et al. (2007) White matter fiber tractography and color mapping of the normal human cerebellum with diffusion tensor imaging. J Neuroradiol 34:115-28|
|Richards, Anna; van den Maagdenberg, Arn M J M; Jen, Joanna C et al. (2007) C-terminal truncations in human 3'-5'DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 39:1068-70|
|Sicotte, N L; Salamon, G; Shattuck, D W et al. (2006) Diffusion tensor MRI shows abnormal brainstem crossing fibers associated with ROBO3 mutations. Neurology 67:519-21|
|Salamon, N; Sicotte, N; Alger, J et al. (2005) Analysis of the brain-stem white-matter tracts with diffusion tensor imaging. Neuroradiology 47:895-902|
|Jen, Joanna C; Chan, Wai-Man; Bosley, Thomas M et al. (2004) Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304:1509-13|