E. A. Del Bono

Prevalence of mutations in TIGR/myocilin in patients with adult and juvenile primary open-angle glaucoma

We thank the families for their willing participation. J.L.W. is supported by NIH grants EY10886 and EY09847, Research to Prevent Blindness, and the Massachusetts Lions; D.V. is suported by NIH grant EY11405, the American Health Assistance Foundation, and the March of Dimes Birth Defects Foundation.

Role of genetic factors in the etiology of juvenile-onset myopia based on a longitudinal study of refractive error.

In an attempt to determine the role of genetic factors in the development of myopia, we examined the relationship of infantile refractive error and parental history to juvenile-onset myopia and analyzed 43 pedigrees affected by juvenile-onset myopia. Refraction data collected at regular intervals from a sample of juvenile subjects participating in a 24-year longitudinal study of refractive error were used. Results showed that children with two myopic parents were 6.42 times as likely to become myopic as children with one or no myopic parents. Furthermore, children who had refractions in the lower half of the distribution at 6 to 12 months of age were 4.33 times as likely to develop myopia as children who had refractions in the upper half of the distribution at 6 to 12 months of age. The pedigree analysis indicated that 63% of individuals considered at risk for developing juvenile-onset myopia actually became myopic, with an equal number of affected males and females. These results suggest that juvenile-onset myopia of moderate amounts may be inherited as a complex trait involving both genetic and environmental factors.

Founder mutations of CYP1B1 gene in patients with congenital glaucoma from the United States and Brazil

Primary congenital glaucoma is an important cause of childhood blindness worldwide. In congenital glaucoma, the anterior segment of the eye fails to develop completely; this results, in particular, in malformation of the trabecular meshwork and aqueous outflow pathways.1,2 Although sporadic cases arise frequently, many cases of congenital glaucoma are inherited as an autosomal recessive trait, and the disease is common, particularly in countries in which consanguinity is customary.3 One gene responsible for autosomal recessive congenital glaucoma, CYP1B1 , has been discovered.4,5 This gene codes for cytochrome P450 1B1, a monooxygenase that may be involved in the metabolism of a variety of substrates, including steroids and retinoids.6 Although the role the gene product plays in congenital glaucoma is not well understood, the protein is likely to be responsible for the metabolism of another compound or compounds that perform critical functions in the developing eye. Interestingly, heterozygous carriers of mutations of CYP1B1 do not have clinically evident ocular or systemic phenotypic abnormalities.7 The CYP1B1 gene is composed of three exons, two of which are translated to produce the protein. Mutations that cause congenital glaucoma have been found in exons 2 and 3. Missense and frameshift mutations have been identified, with most of the missense mutations occurring in highly conserved functional regions of the gene.8 Mutations were first found in this gene in a population of Turkish patients with congenital glaucoma.4 Subsequently, different mutations have been found in a variety of ethnic groups, including Saudi Arabians, Japanese people, and Slovakian gypsies.5,9–11 Most of the mutations of CYP1B1 in patients with congenital glaucoma have been identified in ethnically homogeneous populations. In an earlier study, we screened American and Brazilian families with congenital glaucoma for mutations of the CYP1B1 gene to determine the …

Adult-onset primary open angle glaucoma does not localize to chromosome 2cen-q13 in North American families

Glaucoma is one of the leading causes of irreversible blindness in the world and is characterized by elevated intraocular pressure, optic nerve atrophy, and progressive visual field loss. Primary open angle glaucoma (POAG) is the most common subtype of glaucoma in the United States. Recently, Stoilova and coworkers [Genomics 1996;36:142–150] identified a locus for POAG on chromosome 2 (2cen-q13) in families primarily located in the United Kingdom. We examined families with POAG identified within the US for linkage to the 2cen-q13 locus. A total of 18 families with POAG were used in the analysis. Of 77 family members, 46 were classified as affected and 31 were either glaucoma suspects or considered normal. Eight highly polymorphic and informative markers flanking and distributed throughout the region were used. Parametric lod score analysis was performed using both a dominant and recessive low penetrance or ‘affecteds-only’ model. Multipoint affected sibpair exclusion mapping was also performed. Lod score (both models) and sibpair analysis excluded linkage of the POAG phenotype to the 2cen-q13 region in these families. These data suggest that the chromosome 2cen-q13 locus does not explain a substantial amount of genetic variation in familial POAG.

A genomewide scan identifies novel early-onset primary open-angle glaucoma loci on 9q22 and 20p12

The common form of adult-onset primary open-angle glaucoma is inherited as a complex trait, whereas the rarer early-onset juvenile open-angle glaucoma (JOAG) exhibits autosomal dominant inheritance. Of all cases of JOAG, approximately 10% to 20% are caused by mutations in the myocilin gene. The authors have identified 25 pedigrees that are affected with typical JOAG and that demonstrate autosomal dominant inheritance. They sequenced the myocilin gene in probands from each family and found mutations in 8% of that population. To identify novel genes responsible for JOAG, they used families that did not have myocilin mutinous for a genomewide screen. Markers located on chromosomes 9q22 and 20p12 showed evidence for linkage, identifying two novel loci for early-onset open-angle glaucoma.—Hans E. Grossniklaus

Myocilin Mutations in Families with Late-Onset Primary Open-Angle Glaucoma

Late-onset primary open-angle glaucoma (POAG) is a bilateral disease, which typically has its onset in the fifth or sixth decade of life. The clinical course usually consists of mild to moderately elevated intraocular pressure (IOP), although a significant number of patients may not have a measured IOP greater than the normal range [1]. Optic nerve damage and visual field loss, which may culminate in blindness, occur over many years, usually decades after onset of the disease. The mode of inheritance for late-onset POAG is not known. POAG is considered a complex trait that results from interaction of multiple genes in conjunction with environmental influences.