To gain insight into the pathogenesis of oculomotor disease and strabismus, we are investigating the genetic basis of congenital eye movement disorders referred to as 'congenital cranial dysinnervation disorders' (CCDDs) and studying how these genetic defects perturb development of the oculomotor lower motor neuron system. The neuropathologic findings in Duane syndrome and CFEOM1 and the role of the CFEOM2 gene, PHOX2A (ARIX), in midbrain development support the hypothesis that these disorders result from aberrant development of motor neurons or axonal targeting of cranial nerves with secondary extraocular muscle dysinnervation. We propose that CFEOM and ptosis result from maldevelopment of oculomotor and trochlear nuclei and nerves, Duane syndrome (DS) results from maldevelopment of abducens motoneurons, and horizontal gaze palsy (HGP) results from maldevelopment of abducens motoneurons and interneurons. We have defined five CCDD genetic loci and identified PHOX2A and SALL4 as the genes mutated in CFEOM2 and Duane radial ray syndrome, respectively. We are in the process of positionally cloning the remaining CFEOM genes. In this grant, we seek funding to identify two genes mutated in Duane syndrome (DURS1 and DURS2) and a gene mutated in horizontal gaze palsy with progressive scoliosis (HGPPS). By identifying these genes that cause complex horizontal strabismus we will define the genetic basis of these disorders, develop a tool with which to study their molecular etiologies, and gain important insight into the pathogenesis of oculomotor disease and abducens nuclear and nerve development. We will address these Aims by (1) Identifying the HGPPS disease gene and analyzing pedigrees for disease-causing mutations. (2) Identifying the DURS2 disease gene and analyzing pedigrees for disease-causing mutations. (3) Defining a new DURS1 cytogenetic breakpoint and determining if mutations in candidate DURS1 genes cause DS. (4) Determining if mutations in the identified DS and HGPPS genes cause sporadic DS and/or more common forms of horizontal strabismus. And (5) Initiating structural and functional characterization of the horizontal CCDD genes and their protein products.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015298-02
Application #
6848027
Study Section
Special Emphasis Panel (ZEY1-VSN (04))
Program Officer
Chin, Hemin R
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$405,000
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Shaaban, Sherin; MacKinnon, Sarah; Andrews, Caroline et al. (2018) Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect. Invest Ophthalmol Vis Sci 59:4054-4064
Baris, Hagit N; Chan, Wai-Man; Andrews, Caroline et al. (2013) Complex cytogenetic rearrangements at the DURS1 locus in syndromic Duane retraction syndrome. Clin Case Rep 1:
Högen, Tobias; Chan, Wai-Man; Riedel, Eva et al. (2012) Wildervanck's syndrome and mirror movements: a congenital disorder of axon migration? J Neurol 259:761-3
Webb, Bryn D; Shaaban, Sherin; Gaspar, Harald et al. (2012) HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice. Am J Hum Genet 91:171-9
Chan, Wai-Man; Miyake, Noriko; Zhu-Tam, Lily et al. (2011) Two novel CHN1 mutations in 2 families with Duane retraction syndrome. Arch Ophthalmol 129:649-52
Engle, Elizabeth C (2010) Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol 2:a001784
Rankin, Jessica K; Andrews, Caroline; Chan, Wai-Man et al. (2010) HOXA1 mutations are not a common cause of Möbius syndrome. J AAPOS 14:78-80
Miyake, Noriko; Andrews, Caroline; Fan, Wen et al. (2010) CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome. Am J Med Genet A 152A:215-7
Murillo-Correa, Claudia E; Kon-Jara, Veronica; Engle, Elizabeth C et al. (2009) Clinical features associated with an I126M alpha2-chimaerin mutation in a family with autosomal-dominant Duane retraction syndrome. J AAPOS 13:245-8
Oystreck, Darren T; Khan, Arif O; Vila-Coro, Antonio Aguirre et al. (2009) Synergistic divergence: a distinct ocular motility dysinnervation pattern. Invest Ophthalmol Vis Sci 50:5213-6

Showing the most recent 10 out of 17 publications