Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function.

Down syndrome cell adhesion molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

Utility of molecular testing for related retinal dystrophies.

BACKGROUND: The purpose of this study was to describe our experience with the clinical effects of molecular genetic testing for retinitis pigmentosa (RP) and related retinal dystrophies. METHODS: Chart review of 303 consecutive patients with retinal dystrophies was done when blood was sent for molecular genetic testing between 1993 and 2001. Phenotype information was retrieved for patients with identified mutations. The yield of positive and clinically useful results was assessed. RESULTS: Participants comprised 35 patients with Leber congenital amaurosis, 18 with Usher syndrome, and 250 with isolated RP or other retinal dystrophies. Of these 303 participants, 203 (67%) received positive or negative results of molecular testing for an average of 2.7 genes. Positive results were available in 19 patients after an average time interval of 38+/-22 months (median 33 months, range 1-89 months). No results were received for 84 (28%) patients. In 16 (5%) cases, patients received partial results. Only 19 (6%) patients were found to have sequence changes in RHO, RDS, CRB1, or USH2A, 2 of which were thought to be disease-causing. Only 2 sequence changes were previously documented mutations, but several other novel changes were suspected to be disease-causing mutations also. INTERPRETATION: Molecular testing was helpful only in the minority of cases, largely because of a lack of availability, as well as the complexity of the molecular genetics of RP. Improvements in funding, infrastructure, and molecular knowledge will be necessary to improve the transformation of molecular genetic testing into a clinically relevant bedside tool.