Monday, February 12, 2007

Section 11-C(2): Primary open angle glaucoma

Primary open angle glaucoma (POAG) is the most common form of glaucoma in the United States. Like juvenile onset open angle glaucoma (JOAG), there is also a genetic basis to POAG. However, there are important differences between the genetics of POAG and JOAG. POAG runs in families, but the pattern of inheritance is more difficult to recognize. Due to the relatively late onset of disease in POAG (after the age of 40), most of the families with this condition only include one or two generations of affected family members that are alive. Parents of affected family members are often deceased and offspring of affected members are frequently too young to show signs of the disease. Consequently, families with inherited forms of POAG are generally small with only a few affected members and are difficult to distinguish from sporadic (non-familial) cases (Figure 11-3).

figure 11-3

Figure 11-3 POAG pedigree. This diagram shows an example of the pattern of inheritance of glaucoma may occur in a POAG pedigree. The squares represent male family members, while the circles represent female family members. Darkly shaded symbols indicate an affected family member, while unshaded symbols indicate an unaffected family member. Grey symbols indicate a family member with unknown glaucoma status. Diagonal lines (through a square or circle) indicate that a particular family member is deceased. Notice that the founders of the family are deceased and it is unknown whether they were affected with POAG (indicated by grey boxes). Similarly, most of the grandchildren of the founders are younger than the age at which most people develop glaucoma. It is unknown whether these family members will later develop glaucoma so they are shaded grey to indicate their unknown glaucoma status. The majority of family members affected with POAG are in a single generation.

Although research has indicated that POAG is heritable, most of the genes that cause this disease have not yet been identified. It is likely that some cases of POAG will be due to defects in a single gene, while other cases will be due to the combined effects of mutations in several genes and other environmental factors.

The identification of disease-causing genes has been an active focus of research studies of POAG. The approximate position in the genome, or locus, of many genes that can cause POAG has been determined by linkage analysis (Table 11-3). Loci for genes that cause POAG are designated by the a code beginning with the letters “GLC1” and ending in a suffix letter for each new glaucoma loci in chronologic order of discovery. For example, GLC1A was the first open angle glaucoma locus to be discovered. The glaucoma genes in two of these loci have been discovered (myocilin at the GLC1A locus and optineurin at the GLC1E locus). Research to find the disease-causing genes at the other loci is ongoing.

Chromosomal Loci

Locus Name

Known Gene

Glaucoma

Chromosome 1q

GLC1A

MYOC

JOAG, POAG

Chromosome 2q

GLC1B

-

POAG

Chromosome 3q

GLC1C

-

POAG

Chromosome 8q

GLC1D

-

POAG

Chromosome 10p

GLC1E

OPTN

NTG

Chromosome 7q

GLC1F

-

POAG

Chromosome 5q

GLC1G

-

POAG

Chromosome 2p

GLC1H

-

POAG

Chromosome 15q

GLC1I

-

POAG

Chromosome 9q

GLC1J

-

POAG

Chromosome 20p

GLC1K

-

POAG

Chromosome 2p

GLC3A

CYP1B1

PCG

Chromosome 1p

GLC3B

-

PCG

Table 11-3. Known loci (chromosome location) for primary forms of glaucoma. The chromosomal locations of 13 genes that cause glaucoma have been discovered. The type of glaucoma associated with each loci is indicated: Primary open angle glaucoma (POAG), juvenile-onset open angle glaucoma (JOAG), normal tension glaucoma (NTG), or primary congenital glaucoma (PCG). The disease-causing gene at three of these loci are known, while the remaining ten are as yet undiscovered.

At present, only one gene that causes POAG has been discovered (the myocilin gene at the GLC1A locus). As discussed above, one set of mutations in the myocilin gene are known to cause early onset glaucoma (JOAG). A different set of mutations in the same myocilin gene can cause POAG. In fact mutations in the myocilin gene have been shown to be responsible for approximately 3-4% of worldwide cases of POAG. Myocilin associated glaucoma is inherited as an autosomal dominant trait and offspring of affected parents have a 50% chance of inheriting an abnormal myocilin gene, which confers a high risk for developing glaucoma.

Myocilin defects have been identified in patients with POAG from different races and ethnicities including Caucasians from Midwestern America; Caucasians from Canada; Caucasians from Australia; African Americans from New York City; and Asians from Gifu, Japan. In all populations approximately 1 in 25 cases of POAG are due to abnormalities of the myocilin gene. One set of defects in the myocilin gene cause JOAG while a different set of defects cause POAG. In many cases, when a particular defect in the myocilin gene is detected, the severity of the associated glaucoma (age of onset and maximum intraocular pressure) may be accurately predicted.

Myocilin mutations account for approximately 1 in 25 cases of primary open-angle glaucoma. It is likely that many additional genes are involved in the development of glaucoma. The search for these genes is an area of ongoing research.


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