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Genetic Research

Current Research

Two Types of Fuchs

As discussed on the genetic history page, in 1979 a family with Fuchs Endothelial Corneal Dystrophy (FECD) was described that was different from other families with the disease.  This family showed signs of FECD very early in life.  In addition, the same numbers of males as females were affected with the disease. 

This family was different from what other eye doctors had found in their Fuchs patients.  Previously, FECD had been accepted as a disease that affects individuals approximately 40 years old or older.  In addition, FECD was thought to be more common in women than men. 

Recent research at the Wilmer Eye Institute resolved this controversy by showing that there are two distinct types of FCD. 

Late Onset Fuchs is the type of FECD that is more common.  It affects people in their 40s or older, and seems to affect more women than men.   

Early Onset Fuchs is the type of FECD is rare as we have found it in only one of 64 families.  This types of Fuchs dystrophy affects people when they are young.  In addition, it can affect the sexes in equal numbers. 

You can read the research paper on this subject by following this link. 

Phenotypes and Genotypes

Phenotype:  The observable traits or characteristics of an organism, for example, hair color, weight, or the presence or absence of a disease.  Phenotypic traits are not necessarily genetic.  (Definition from:  National Human Genome Research Institute at the National Institutes of Health.)

Genotype:  One’s genetic identity as defined by one’s DNA (genes). 

A person’s genotype has a strong influence on what phenotype that person exhibits.  Not all phenotypes are visible. 

How Does a Mutation Affect Genotypes and Phenotypes?

You may wish to review the DNA section of this website.

DNA is the genetic code, the “instruction manual,” that tells cells how to put together amino acids.  Amino acids are the building blocks of proteins.  These amino acids stick together and bend around each other into shapes to create proteins. 

Collagen is a protein.  There are many types of collagen in the human body.  Each type of collagen is encoded for by a different section (gene) of the instruction manual (DNA). 

When there is a mistake in the DNA, we call it a mutation.  Sometimes, these mistakes are very small, kind of like a one letter typo in an instruction manual, so the instructions don’t actually get misread.  The machinery in the cell can still tell what the DNA meant to write in the instruction manual.  The building blocks (amino acids) still get put together in the right way, and the final product (the protein) still looks and behaves the way it’s supposed to.  In this situation, the genotype has been altered, but the phenotype, remains the same. 

However, sometimes, the DNA mutation (mistake in the DNA) is a really big mistake in the instruction manual.  Think of it like a page falling out of the instruction manual.  If the mutation is this severe, the protein will not be made correctly.  In that situation, the genotype (DNA code) has been altered, leading to a change in the phenotype (the way the protein looks and acts).  This may lead to change in the protein function and may cause a particular disease. 

The Two Types of FCD Have Different Genotypes 

In 2001, researchers in England published a report detailing a mutation (change) in the DNA of people in one family with FCD.  (Follow the link for the report by Biswas, et al.)  The technical name for the area of DNA that was mutation is: “The 6-7 cM region on chromosome 1p34.2-p32.” At location 455, what is normally the amino acid glutamine Amino Acid glutamine gets changed to the amino acid lysine Amino Acid lysine

In 2003, researchers at the Wilmer Eye Institute published a report detailing their discovery of a mutation in the DNA of people in a family in the United States who had early onset FECD.  (Follow the link for the report by Gottsch, et al.)  This mutation causes location 450 that changes amino acid Leucine Amino Acid leucine to amino acid Tryptophan Amino Acid tryptophan.

The researchers in England and America found mutations in slightly different locations, but both mutations lay within the gene for COL8A2. 

This meant that the next step was to see if this mutation was affecting the phenotype.  In other words, was the mutation in DNA causing these individuals to develop Fuchs dystrophy?

The graph below shows that patients with a mutation in COL8A2 developed Fuchs dystrophy earlier in life than Fuchs patients without a mutation in COL8A2.

Graph of FECD
Graph of the severity of FECD versus age.

Squares: males, Circles: females.

Solid symbols:  Have COL8A2 mutation.

Clear symbols:  Do not have 
mutation in COL8A2.

Photos of Corneas
Electron Microscope Photos of Corneas

This figure demonstrates the thickening of the cornea that occurs in Fuchs dystrophy.  These phenotypic changes may be a direct result of the genotypic changes that occur to the DNA.            

These images also demonstrate the phenotypic differences between normal corneas and those with early- and late-onset Fuchs dystrophy.  These are images of fresh sections, though, whereas the images above are of prepared sections.

Phenotypic differences between normal corneas and

Late Onset

Late Onset of the Endothelium

Comfocal Spectrometry Images of the Endothelium

Early Onset

Early Onset of the Endothelium

Late Onset

Late Onset Slit Lamp Cornea

Slit Lamp Images of the Cornea

Early Onset

Early Onset Slit Lamp Cornea


One issue that is not clear is how mutations in COL8A2 lead to the actual disease, Fuchs Dystrophy.   However, there are some ideas.  Collagen VIII is part of the extracellular matrix.  In general, the job of the extracellular matrix is to provide physical support for tissues in the body.  There is evidence that Collagen VIII may not only act as a general structural fiber, but may also do special jobs during cellular differentiation (the making of new cells).  It has been suggested, therefore, that mutations in collagen VIII may lead to disruptions in the process that normally creates new endothelial cells.  It has also been suggested that the mutations in Collagen VIII may lead to structural abnormalities in Descemet's membrane (the layer of cornea between the endothelium and the stroma).

For more information on how mutations are associated with disease:  


Serial Analysis of Gene Expression (SAGE) is a laboratory method for figuring out what messenger RNA (mRNA) is being made in particular cells, and how much of this mRNA is being made in the cells. 

mRNA Tag

cDNA Tags
Probe Tags

Microarray Tag

Recently, SAGE analysis was used to compare what proteins were being produced in Fuchs corneas and what proteins were being produced in normal (healthy) corneas.  Two very striking differences were found.  First, the level of mitochondrial DNA was severely underexpressed in corneas with Fuchs dystrophy.  Second, the level of antioxidants such as glutathione was also underexpressed in these corneas.      

Proper vision is highly dependent on proper endothelial function to maintain an appropriate amount of stromal hydration. Excess fluid in the stroma leads to swelling and reduces corneal clarity. The endothelium regulates the flow of fluid into the stroma through the use of sodium-potassium ion channels. A large supply of ATP is necessary for these ion channels to function properly. Because mitochondria is responsible for producing ATP, downregulation of mitochondria could potentially lead to ineffective ion channels and subsequent stromal swelling.

Antioxidants play an essential role in proper endothelial function by regulating the amount of reactive oxygen species (ROS).  An abundance of reactive oxygen species can cause oxidative stress, which is damaging to endothelial mitochondria.  SAGE analysis of Fuchs' diseased eyes showed a downregulation of antioxidants such as glutathione, which would subsequently lead to mitochondrial failing and inefficient ion channels.

To read more about SAGE, go to CorneaNET.

You can read more about SAGE techniques at 

To read a scientific paper in which researchers at the Wilmer Eye Institute used SAGE to investigate Fuchs corneas, follow the link.

Sanford Greenberg Elected to the American Academy of Arts and Sciences

Dr. Jennifer Thorne Appointed President-elect of American Uveitis Society- 5/17/16

Dr. Ingrid Zimmer-Galler Elected to the ATA College of Fellows- 5/13/16

Dr. Arevalo Launches New Book at ARVO 2016- 5/09/16

Dr. Elia J. Duh is elected to the American Society for Clinical Investigation- 4/28/16

Dr. Maria Valeria Canto Soler Wins BrightFocus Award for Macular Degeneration Research- 4/27/16

Three Wilmer Faculty Voted Most Influential in Field of Ophthalmology- 4/22/2016

Dr. Pradeep Ramulu Wins Pisart Award for Significant Achievement in Vision Science Research- 4/21/16

Dr. Eghrari Receives Alcon Early Career Research Award- 4/13/16

Dr. Quigley Honored by American Glaucoma Society- 4/11/16

Dr. Ian Pitha Awarded Grants for Glaucoma Research- 4/11/16