Molecular Basis of Congenital Strabismus

A significant portion of congenital mental retardation is believed to result from errors in the development of the central nervous system.  Understanding and preventing these disorders will require greater knowledge of neuro-development. A powerful approach to gain insight into the development of this complex system is to study the molecular basis for relatively simple genetic diseases that disrupt the system. Toward this goal, we are studying a group of inherited disorders of eye movement, referred to as the ‘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, ROBO3, and HOXA1). 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 (HOXA1 and PHOX2A), and axonal targeting of the extraocular muscles (KIF21A). This grant supports our continued work to discover the genetic causes of vertical CCDDs beyond PHOX2A and KIF21A, 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. Our Aims are as follows: 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 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.