AVN Members : Dr. Joe Casey
My Lab’s passion is membrane transport. How do membrane transport proteins move substances into and out of cells? How do diseases happen when the transport process fails? In particular, we are interested in corneal dystrophies caused by failure to move fluid out of the human cornea. Our specific interest is in the function of a protein, SLC4A11, whose defects cause the three genetic corneal dystrophies described below.
SLC4A11 is an integral membrane transport protein, found on the basolateral surface of corneal endothelial cells. It acts as a water and ammonia transporter.
Since the cornea forms the outer wall of the eye and provides twice as much refractive power as the lens, corneal disorders result in profound visual defects. The cornea also presents a defensive barrier for the remainder of the eye. An examination of the multi-layer structure of the cornea helps to explain how it achieves its roles. The stroma, composed of an extremely high concentration of proteoglycans and collagen, is almost acellular and thus clear. The stroma’s high level of solutes results in a strong osmotic driving force to accumulate fluid. Osmotic pressure in the stroma provides physical protection to the rest of the eye. Importantly the osmotic pressure is balanced by the “pumping” action provided by ion transport in the highly metabolically active endothelial cell layer underlying the stroma. The corneal endothelium moves ions from the stroma to the aqueous humour, resulting in osmotic fluid movement countering fluid movement into the stroma. In healthy cornea, fluid movement into and out of the stroma is balanced perfectly by the endothelial layer without excessive fluid accumulation. In ECD, fluid balance is not achieved, causing visual defects.
Fuchs Endothelial ECD (FECD)
FECD is the most common cause of corneal transplant, accounting for up to 25% of corneal grafts in Canada and other Western countries. Among people over age 40, 4% develop this dominantly-inherited, progressive disease. FECD is, however, genetically heterogeneous, and two other genes have been reported as responsible for some early-onset FECD. Nonetheless, at least 5% of FECD cases arise from mutations of SLC4A11, implying that tens of thousands of Canadians will suffer from FECD because of defects in SLC4A11. FECD is characterized by corneal fluid accumulation, causing serious decline of visual acuity, described as “hazy” or “cloudy”, and is associated with cataracts. FECD etiology centres on the corneal endothelium, the structure responsible for H2O reabsorption from the corneal stroma. Endothelial cell density declines in FECD and the Descemet membrane underlying the endothelial layer develops “bubbles” on its surface that are termed “guttae”. Patients with FECD have swollen rough ER in their corneal endothelial layer, with signs of ER-stress, consistent with our observations of ER-retention of misfolded SLC4A11 disease mutants.
Congenital Hereditary Endothelial Dystrophy (CHED)
CHED is a serious, but relatively uncommon recessive genetic disease, developing in utero and present at birth. Reflecting the recessive inheritance of the disorder, the incidence of CHED is elevated in areas where consanguinity is common, where 13-35% of corneal transplants are to treat CHED. In CHED the cornea is severely edematous, up to three times thicker than normal. Visual acuity is reduced to the light perception level.
Harboyan Syndrome (HS)
HS is essentially a variant of CHED again presenting early in life, with the addition of sensorineuronal deafness. HS is caused by a distinct set of mutations, however, the reason why some SLC4A11 mutations induce CHED and others HS is presently unknown.