Researchers from the John T. Macdonald Department of Human Genetics and the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine have found that inherited mutations in the MINAR2 gene cause deafness in four families. The genetic variation primarily affects hair cells in the inner ear, which are essential for hearing.
The authors believe that the progressive nature of this hearing loss, in some affected individuals and in mice, may offer treatment opportunities. The study, titled “Mutations in MINAR2 encoding the integral membrane NOTCH2-associated receptor 2 cause deafness in humans and mice,” was published online June 21 in the journal PNAS (Proceedings of the National Academy of Science).
“MINAR2 plays a major role in hearing, and these inherited mutations lead to sensorineural deafness,” said Mustafa Tekin, MD, professor in the Department of Human Genetics at the Dr. John T. Macdonald Foundation and senior author of the paper. . “The results suggest that these cases may be suitable for intervention with gene therapies.”
Dr. Tekin has studied the genetic basis of hearing loss for more than 20 years and has established a biorepository with a genomic sequencing database of genetic mutations associated with deafness in families around the world.
“We first look at known genetic mutations,” said Dr. Tekin, who is also head of the clinical and translational genetics division, director of the biochemical and molecular genetics diagnostic laboratory and professor of otolaryngology. . “If we don’t find any, we do whole genome sequencing to potentially identify new genes or something that we may have missed in the initial test.”
DNA variants found
In this study, the team sequenced the genome of a Turkish family, targeting known deafness genes, but found nothing. Following whole genome sequencing, they found DNA variants in MINAR2, which had only recently been described in the research literature. Scientists are still filling in the gaps about the function of the gene.
After identifying MINAR2 variations in one family, Dr. Tekin’s team searched their database and found a second family with a different mutation in the same gene. Further investigation confirmed their findings in animal studies and identified three different MINAR2 mutations, which caused deafness in 13 people from four families.
We discovered that this gene performs an important function. The protein localizes to hair cells and other areas essential for hearing. Future research will focus on clarifying the role of the gene.
Mustafa Tekin, MD, Professor, Department of Human Genetics, Dr. John T. Macdonald Foundation
Hair cells convert sound into electrical signals, which are then sent to the brain. Normally, when children are born deaf, they have few or no living hair cells. As a result, gene therapies and other regenerative efforts would likely fail. However, in the MINAR2 knockout mouse model, the hair cells remain alive until later in life. This progressive loss of hearing could allow treatment.
“What is surprising and promising for a potential intervention is that when we looked at the hair cells in our mouse model, they are alive until a certain age,” Tekin said. “It gives us a window of opportunity to provide treatment. We could insert the normal gene and potentially restore hearing.
University of Miami Miller School of Medicine
Bademci, G., et al. (2022) Mutations in MINAR2 encoding membrane-embedded NOTCH2-associated receptor 2 cause deafness in humans and mice. PNAS. doi.org/10.1073/pnas.2204084119.