Mutations Identified in High-Grade Myopia

Ricki Lewis, PhD

May 09, 2013

Mutations in a gene that controls copper metabolism in parts of the eye are linked to the severe, high-grade form of the myopia, according to results from a study published in the May 2 issue of the American Journal of Human Genetics.

High-grade myopia, with refractive error exceeding −6.00 D, runs in families and affects approximately 2% of the 33.1% of adults in the United States with myopia. It is associated with increased risk for retinal detachment, glaucoma, cataracts, and disease of the macula.

Khanh-Nhat Tran-Viet, MS, laboratory manager at the Duke Center for Human Genetics in Durham, North Carolina, and colleagues used next-generation exome sequencing of 4 members of an 11-member, 3-generation family of European descent. Nine members of the family have autosomal-dominant, nonsyndromic high-grade myopia, with an average spherical refractive error of −22.00 D.

The 4 sequenced exomes shared rare gene variants at 49 loci. The investigators then used Sanger-sequencing to analyze the variants in the other family members, including the remaining 5 affected individuals.

The relatives with high-grade myopia share a nonsense mutation in SCO2, a gene that encodes a cytochrome c oxidase assembly protein, which functions in the mitochondrial respiratory chain. Substitution of glutamine with a stop codon at position 53 truncates the protein, eliminating the catalytic domain.

The researchers then used polymerase chain reaction sequencing to analyze SCO2 in 140 unrelated cases and found 3 additional mutations. In contrast, the team found no similar mutations in 1000 control DNA samples from nonmyopic individuals.

The SCO2 protein normally carries copper in the mitochondria, and its malfunction enables reactive oxygen species to accumulate and damage DNA and ocular tissues. The phenotype affects the retina because of its high energy requirement. Damage to the retina, in turn, alters refractive development, the researchers write.

Follow-up studies further implicated the gene. The researchers tracked SCO2 gene expression in relevant structures that contribute to myopia and discovered decreased expression of the gene in eyes made myopic with artificial lenses in mice.

Alternate Guise: Infantile Cardiomyopathy

The team's identification of a defect in a copper-binding protein made sense, although they did not set out with any specific candidate genes in mind. "The connection was fortuitous. The literature shows individuals who have copper deficiency tend to become nearsighted, and we found a gene that has to do with copper metabolism," Terri L. Young, MD, MBA, professor of ophthalmology, pediatrics and medicine at the Duke Eye Center and principal investigator, told Medscape Medical News. The finding is consistent with the observation that depriving certain animal models, such as rats, of copper leads to ocular abnormalities.

Moreover, compound heterozygotes for missense mutations in the SCO2 gene have fatal infantile cardioencephalomyopathy, a more severe phenotype than that of the individuals with a single nonsense mutation. The cardiomyopathy syndrome includes retinal ganglion neuronal loss and globular distension of the photoreceptors. The infants die too soon to investigate refractive error.

The SCO2 gene did not emerge in other studies of causes of high-grade myopia, such as those that identified a zinc finger protein. "[O]ur findings provide evidence that SCO2 may play an important role in eye growth and development, particularly in those who become highly myopic," the researchers conclude.

Because the SCO2 form of high-grade myopia may be a very rare subtype, screening for it alone does not make sense, Dr. Young said. "We're developing a panel of genes implicated in syndromic and nonsyndromic myopia," she added, such as screens for the 18 genes that cause Leber congenital amaurosis. She also suggested that copper supplements may help prevent some forms of myopia.

The work on this rare genetic subtype of a common condition has broader implications, according to Dennis J. Thiele, PhD, George Barth Geller professor in the Department of Pharmacology and Cancer Biology at Duke University, who was not part of the study. "It clearly implicates copper homeostasis in myopia and suggests that in the absence of mutations, dietary copper deficiency could be in part responsible for myopia," he told Medscape Medical News. He cautioned that although copper is an essential micronutrient, too much is toxic.

Shalom Kieval, MD, associate clinical professor of ophthalmology at Albany Medical College in New York, places the work in perspective. "Myopia development is a complex process that emerges from the interplay of both genetic and environmental factors," he said, citing recent work suggesting that lack of sunlight contributes to myopia in children. "As we deepen our understanding of the mechanisms that induce myopia, we can expect to develop clinical and public health interventions to reduce the great social and economic burden of the disease," he added.

This research was funded by the National Institutes of Health, the Lew Wasserman Award from Research to Prevent Blindness, and a Duke–National University of Singapore core grant. One coauthor was supported by the Toulouse Hospital Young Researcher Fellowship, the Fondation pour la Recherche Médicale, and Fondation de France. The animal model experiments were supported by the National Medical Research Council of Singapore. The commentators have disclosed no relevant financial relationships.

Am J Hum Genet. 2013;92:820-826. Abstract