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

P rimary 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. 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. One gene responsible for autosomal recessive congenital glaucoma, CYP1B1, has been discovered. 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. 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. 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. Mutations were first found in this gene in a population of Turkish patients with congenital glaucoma. Subsequently, different mutations have been found in a variety of ethnic groups, including Saudi Arabians, Japanese people, and Slovakian gypsies. 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 frequency of mutations of CYP1B1 in patients with congenital glaucoma in ethnically diverse populations: 3/21 families had mutations of CYP1B1 (Finzi S, Figureiredo Sena D, Del Bono E, Haines JL, Wiggs JL. Clinical phenotypes associated with CYP1B1 mutations in patients with congenital glaucoma from the U.S. and Brazil. Manuscript submitted). Interestingly, all of the mutations we found had been identified previously in other populations (and two were found in the American and Brazilian patients in this study). Recurrent mutations have been described in patients with many human diseases, including cystic fibrosis, breast cancer associated with mutations in BRCA2 and juvenile glaucoma associated with mutations in TIGR and Myocilin genes. The recurrence of a particular mutation may be the result of a ‘‘hot spot’’ for a mutation, such as CpG dinucleotides. Alternatively, the same mutation may be found in unrelated patients because of migration of a founder chromosome that carries the mutation. In such cases, the genetic markers on the mutant chromosome would be the same in all occurrences and can be matched across populations. This study aimed to determine whether multiple occurrences of mutations in CYP1B1 are the result of gene regions prone to mutation or the consequence of inheritance of ancient founder chromosomes. Key points