Summary: The researchers identified three different MINAR2 gene mutations that were responsible for deafness in 13 people from four different families.
Source: University of Miami
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 was published June 21 in the journal PNAS.
“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,” Dr. Tekin said. “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.”
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 gene’s function.
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 found that this gene performs an important function,” Dr. Tekin said. “The protein localizes to hair cells and other areas critical for hearing. Future research will focus on clarifying the role of the gene.
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.
About this genetics and deafness research news
Author: Kai Hill
Source: University of Miami
Contact: Kai Hill—University of Miami
Image: Image is in public domain
Original research: Free access.
“Mutations in MINAR2 encoding membrane-integrated NOTCH2-associated receptor 2 cause deafness in humans and mice” by Mustafa Tekin et al. PNAS
Mutations in MINAR2 encoding membrane-embedded NOTCH2-associated receptor 2 cause deafness in humans and mice
The discovery of deafness genes and the elucidation of their functions have contributed considerably to our understanding of the physiology of hearing and its pathologies.
Here we report the DNA variants in MINAR2, encoding the integral membrane receptor 2 associated with NOTCH2, in four families underlying non-syndromic autosomal recessive deafness. Neurological evaluation of affected individuals at ages ranging from 4 to 80 shows no additional abnormalities. MINAR2 is a recently annotated gene with limited functional understanding.
We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10) and c.393G > T, in 13 people with severe to profound congenital or prelingual sensorineural hearing loss (SL) . The c.393G > T variant has been shown to disrupt a splice donor site. We show that Minar2 is expressed in the inner ear of the mouse, the protein localizing mainly in the hair cells, the spiral ganglia, the spiral limbus and the vascular stria.
Mice with Minar2 protein loss of function (Minar2tm1b/tm1b) show rapidly progressive neurosensory LH associated with reduction of outer hair cell stereocilia in the shorter row and hair cell degeneration in later life.
We conclude that MINAR2 is essential for hearing in humans and mice and that its disruption leads to neurosensory LH.
The progressive LH observed in mice and some affected individuals and the relative preservation of hair cells offer the possibility of interfering with LH using gene therapies.