Ophthalmic Genetics and Visual Function Branch

Ophthalmic Genetics and Visual Function Branch
Building 10, Room 10N226
10 Center Drive, MSC 1860
Bethesda, Maryland 20892-1860
Phone: 496-3577
Fax: 402-1214

On this page:

• Mission Statement
• Structure
• Research Overview
• Selected Publications

Mission Statement

The Ophthalmic Genetics and Visual Function Branch plans and conducts clinical and laboratory research of gene expression and molecular interactions important to the eye, and applies clinically relevant research findings to the prevention, diagnosis, and treatment of diseases affecting the eye and visual system, including corneal disease, cataract, retinal diseases, and abnormalities of the visual pathways. Clinical and laboratory approaches to this research will be coordinated and training opportunities in clinical research methodology will be available.

Structure

(Click on the name of the Section to see its activities)

Research Overview

The vision of the Ophthalmic Genetics and Visual Function Branch is to be indisputably recognized as a centre of excellence for clinical investigation, research and treatment of heritable ocular disorders and to train the next generation of vision scientists.

The Ophthalmic Genetics Branch has a team of skilled and devoted clinician scientists, molecular geneticists, genetic counselors, and technologists, who have at their disposal a strong array of clinical and molecular genetic diagnostic tools for the investigation of families and patients with inherited retinal disorders. Over many years of clinical research, the Branch has compiled an impressive database of patients with fully characterized phenotypic information on a host of heritable ocular disorders. These disorders are then amenable to further molecular genetic analysis and to future treatment protocols. The Branch aims to:

• Develop targeted clinical protocols for heritable ocular disorders.
• Expand a research infrastructure that supports the investigation and molecular genetic diagnosis of heritable ocular diseases. Part of that activity includes oversight of the National Genotyping Initiative (eyeGENE) currently being established by NEI.
• Provide postgraduate training opportunities for the next generation of vision scientists in the investigation and treatment of inherited ocular disorders.

Research Summary

Choroideremia
Choroideremia is caused by mutations in a gene that encodes an escort protein, REP-1, that is necessary for the lipid modification of small ras-related GTPases, called Rab proteins. These proteins are important for normal vesicular trafficking with the cell. Specific research themes are being pursued in the study of this condition including: 1) genotyping of patients who have been given this clinical diagnosis; 2) REP-1 gene expression studies, and studies of the molecular interactions that ensue that will help guide future targeted therapies for CHM; and 3) clinical studies that document the natural history of this condition and account for the preservation of central visual function.

Macular Dystrophy
The study of one family with a dominantly inherited macular dystrophy allowed the mapping and then the discovery of a gene, ELOVL4, which is mutated in affected family members. ELOVL4 is presumed to function in the elongation of very long chain fatty acids, such as docosahexaenoic acid (DHA), which are essential for normal retinal function. In collaboration with colleagues at the University of Alberta, a preclinical trial is planned to study the effect of DHA supplementation on the Elovl4 mouse. Further a clinical trial of DHA supplementation in patients affected by this disorder is planned to occur through the NEI.

Best vitelliform macular dystrophy is another dominantly inherited maculopathy; in this case caused by mutations in the bestrophin gene which is encodes a chloride channel expressed in the retinal pigment epithelium. Controversy still exists as to this concept. We plan to use cell model systems to clarify this question by testing the effect of pharmacologic blockers specific for chloride channels in cells expressing bestrophin mutations.

Other Heritable Eye Disorders
The surgical management of complex strabismus can be challenging. Within this group there is a subset of patients with genetic forms of myopathy, for example, Thomsen's disease. Thomsen's disease or myotonia congenita is a rare inherited muscular excitatory disorder caused by mutations in a chloride channel (CLCN1). The investigation and management of these patients and others offers an opportunity to better understand the effect of conventional strabismus surgery management and improve outcomes.

Selected publications:

McTaggart KE, Tran M, Mah DY, Lai SW, Nesslinger NJ, and MacDonald IM. Mutational analysis of patients with the diagnosis of choroideremia. Human Mutat 20:189-96, 2002.

Lines MA, Hébert M, McTaggart KE, Flynn SJ, Tennant MT and MacDonald IM. Electrophysiologic and phenotypic features of an autosomal dominant cone-rod dystrophy caused by a novel CRX mutation. Ophthalmology 109:1862-70, 2002.

MacDonald IM, Reed G, and Wakeman B. Post-operative diplopia from retrobulbar anaesthesia. Can J Ophthalmol. 2004; 39:267-271.

MacDonald IM, Hébert M, Yau R, Jumpsen J, Suh M and Clandinin MT. The effect of docosahexaenoic acid supplementation on macular function in a patient with autosomal dominant Stargardt-like macular dystrophy. Br J Ophthalmol. 88; 305-6, 2004.

Jacobson SG, Cideciyan AV, Sumaroka A, Aleman TS, Schwartz SB, Windsor EA, Roman AJ, Stone EM, MacDonald IM. Remodeling of the human retina in choroideremia: Rab escort protein 1 (REP-1) mutations. Invest Ophthalmol Vis Sci 2006;47:4113-20.