Abstract

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). We have proposed that the forms of CCDD with primary dysfunction of vertical eye movement, including CFEOM and ptosis, result from maldevelopment of oculomotor and trochlear nuclei and nerves, while the forms of CCDD with primary dysfunction of horizontal gaze, including Duane syndrome and horizontal gaze palsy, result from maldevelopment of the abducens nucleus and nerve. Thus far, we have defined six CCDD genetic loci (FEOM1-3, PTOS1, DRRS, DURS3) and identified all of the CCDD genes known to date (PHOX2A, SALL4, KIF21A, and ROBO3). Each of these genes appears to be essential to a specific step in the development of the ocular cranial nuclei, including axonal targeting of the motor neurons (ROBO3), motor neuron development (PHOX2A), and axonal targeting of the extraocular muscles (KIF21A). In this renewal application, we seek funding to continue our work to discover the genetic causes of vertical CCDDs beyond PHOX2A andKIF21A, including identification of the FEOM3 and PTOS1 genes. By identifying new genes mutated in complex vertical strabismus and ptosis we will define the genetic basis of these disorders, leading both to diagnostic testing for affected individuals and to new avenues of investigation into the pathogenesis of oculomotor disease and cranial nuclear, nerve, and muscle development. We will address the following aims:
Aim 1. Identify the FEOM3 disease gene and analyze CFEOM pedigrees and sporadic individuals for disease-causing mutations.
Aim 2. Identify the PTOS1 disease gene and analyze congenital ptosis pedigrees and sporadic individuals for disease-causing mutations.
Aim 3. Identify new vertical CCDD loci by SNP-based genome screens of unmapped pedigrees.
Aim 4. Initiate structural and functional characterization of the FEOM3 and PTOS1 genes and their protein products.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012498-09
Application #
7467383
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Chin, Hemin R
Project Start
1999-05-03
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
9
Fiscal Year
2008
Total Cost
$327,787
Indirect Cost

  Institution

Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Di Gioia, Silvio Alessandro; Shaaban, Sherin; Tüysüz, Beyhan et al. (2018) Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies. Am J Hum Genet 103:115-124
Grant, P Ellen; Im, Kiho; Ahtam, Banu et al. (2018) Altered White Matter Organization in the TUBB3 E410K Syndrome. Cereb Cortex :
Jamuar, Saumya S; Schmitz-Abe, Klaus; D'Gama, Alissa M et al. (2017) Biallelic mutations in human DCC cause developmental split-brain syndrome. Nat Genet 49:606-612
Whitman, Mary C; Engle, Elizabeth C (2017) Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance. Hum Mol Genet 26:R37-R44
Whitman, Mary C; Andrews, Caroline; Chan, Wai-Man et al. (2016) Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development. Am J Med Genet A 170A:297-305
Park, Jong G; Tischfield, Max A; Nugent, Alicia A et al. (2016) Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects. Am J Hum Genet 98:1220-1227
Khan, Arif O; Almutlaq, Mohammed; Oystreck, Darren T et al. (2016) Retinal Dysfunction in Patients with Congenital Fibrosis of the Extraocular Muscles Type 2. Ophthalmic Genet 37:130-6
Balasubramanian, Ravikumar; Chew, Sheena; MacKinnon, Sarah E et al. (2015) Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome. J Clin Endocrinol Metab 100:E473-7
MacKinnon, Sarah; Oystreck, Darren T; Andrews, Caroline et al. (2014) Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology 121:1461-8
Thomas, Shery; Thomas, Mervyn G; Andrews, Caroline et al. (2014) Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation. Eur J Hum Genet 22:344-9

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