As so many gene discoveries do, this one starts with a patient and his family and a story. In this case, a pediatric ophthalmologist from Montana told Dr. Richard Lewis, professor of ophthalmology at Baylor College of Medicine, about a young boy aged 5 years who came to him with a cataract in one eye. There was no history of injury, but the physician performed an operation to remove the milky lens and replace it with an artificial one.
The next year, the child returned. The eye on which the doctor had operated was fine, but the second now had a milky cataract. When the doctor could talk to the boy’s father, he found that the man was one of 10 children, including seven brothers. Three of these brothers had developed cataracts between the ages of 5 and 8 years. Later, all three had died of sudden cardiac death before the age of 35.
The medical journey to finding which gene was involved was long and, as yet, not finished, but Lewis and his colleagues have persevered, eager to find not only the gene that caused the cataracts but also the source of the sudden death. Combining genomic and genetic techniques, they identified the cataract gene as a mutation of LEMD2, a gene known to be involved in lens development in the eye. In this case, the gene mutation is homozygous, meaning that the person inherits the same mutated gene from each parent. A report on their work appears in the journal Molecular Genetics & Genomic Medicine.
The brothers and their families were all members of a religious sect known as the Hutterites who live in the northern part of the United States or southern Canada. Hutterites are Anabaptists, similar to Mennonites and Amish, persecuted for centuries for their beliefs, particularly their opposition to violence and military service. Hutterites are distinguished because a central tenet of their religion is that they share what they have among members of the community. In the late 1800s, they moved from Russia to the Dakota Territory, where 400 settled in colonies and more than 800 took up individual farms. Over the following years and for various reasons, some moved into Canada and other parts of the northern United States, including Montana.
The cataracts had attracted medical attention in the mid-1980s, but no one had noticed the association with sudden death. When Lewis visited the Montana group, he collected 16 to 18 samples from the original child’s nuclear family, his father’s siblings and the living grandparents. In January 2014, a cousin of the father died suddenly in Canada, giving Lewis a chance to collect more samples – 61 in total, including after protracted legal wrangling, one from the woman who had died. In total, the researchers genotyped 84 family members, including 17 who had cataracts. The difference in the gene is a missense mutation in which a single change in one nucleotide results in an amino acid different from the one made normally. This changes the resulting protein, and, Lewis and colleagues believe, ultimately results in the formation of cataracts.
As part of the work, Dr. Philip Boone (a graduate of Baylor’s M.D. /Ph.D. training program and now a resident at Harvard Medical School Pediatrics/Medical Genetics Combined Residency) and later Dr. Jennifer Posey, a postdoctoral fellow at Baylor, studied the exomes (the protein-forming parts of the genome) in three people in each of three families – a child with cataracts, the mother and the father. Yet the only sample they had from a person with cataracts who had experienced sudden death was the cousin of the first family Lewis studied.
“This is the first time we have had a provable link between this type of cataract and sudden cardiac death,” said Posey. It might be that the cataract gene they identified is the culprit, but they have to prove that, she said.
Others who took part in this work include Bo Yuan, Ph.D., Shen Gu, Ph.D., Tomasz Gambin, Ph.D., Claudia Gonzaga-Jauregui, Ph.D., Mahim Jain, M.D., Ph.D., Janson J. White, B.S., Shalini N. Jhangiani, M.S., Kimberly Walker, M.S., Qiaoyan Wang, M.A., Donna M. Muzny, M.S., Richard A. Gibbs, Ph.D., and James R. Lupski, M.D., Ph.D., all of Baylor; Zhiwei Ma, M.D., Ph.D., and J. Fielding Hejtmancik, M.D., Ph.D., of the National Eye Institute in Rockville, Maryland; and Todd J. Murdock, M.D., of the Rocky Mountain Eye Center in Missoula, Montana.
Funding for this work came from the Baylor College of Medicine Medical Scientist Training Program (Grant T32GM007330), a National Eye Institute (NEI) Training Program grant (T32EY007102) from the United States National Institutes of Health (NIH), and grants from the Wintermann Foundation and the Baylor Research Advocates for Student Scientists, the National Institute of General Medical Sciences (NIGMS) Medical Genetics Research Fellowship Program (Grant T32GM0752637), the organization Research to Prevent Blindness, New York, whose unrestricted funds supported parts of these investigations. This work was supported in part by the National Human Genome Research Institute and National Heart Lung and Blood Institute (NHGRI/NHLBI) to the Baylor–Hopkins Center for Mendelian Genomics (Grant U54HG006542) and NHGRI (Grant U54HG003273).