To screen a population with primary open-angle glaucoma for mutations in the gene
that encodes the trabecular meshwork inducible glucocorticoid response protein (TIGR),
also known as myocilin (MYOC).
Ophthalmologic information was collected for study subjects with primary open-angle
glaucoma and their relatives. Mutation screening of 74 primary open-angle glaucoma
probands was conducted by sequencing TIGR/MYOC coding sequence and splice sites.
In 23 families we detected 13 nonsynonymous sequence changes, nine of which appear
to be mutations likely to cause or contribute to primary open-angle glaucoma. Two
mutations, Arg272Gly and Ile499Ser, and one nonsynonymous sequence variant, Asn57Asp,
are novel. We found mutations in nine of 25 juvenile glaucoma probands (36%) and two
of 49 adult-onset glaucoma probands (4%). Age classification of families rather than
individual probands revealed mutations in three of nine families with strictly juvenile
primary open-angle glaucoma (33%), and no mutations in 39 families with strictly adult-onset
primary open-angle glaucoma (0%). In families with mixed-onset primary open-angle
glaucoma containing both juvenile primary open-angle glaucoma and adult-onset primary
open-angle glaucoma cases, we found mutations in eight of 26 families (31%).
Our data suggest that Gly252Arg, Arg272Gly, Glu323Lys, Gln368STOP, Pro370Leu, Thr377Met,
Val426Phe, Ile477Asn, and Ile499Ser are likely to play roles that cause or contribute
to the etiology of autosomal dominant primary open-angle glaucoma. Our finding of
more TIGR/MYOC mutations in families with mixed-onset primary open-angle glaucoma
than in the families with strictly adult-onset primary open-angle glaucoma implies
that the presence of relatives with juvenile primary open-angle glaucoma in a family
could be used as a basis for identifying a subset of the population with adult-onset
primary open-angle glaucoma with higher prevalence of TIGR/MYOC mutations. To address
this issue, and to refine estimations of mutation prevalence in these age-defined
subpopulations, prospective study of a larger population ascertained entirely through
adult-onset primary open-angle glaucoma probands will be needed.