期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：26
DOI：10.1073/pnas.2204084119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Molecular components of hearing in mammalians are not completely delineated. Via a genetic approach conducted in families with sensorineural hearing loss, this study presents MINAR2 as an indispensable element of hearing in humans. Similarly, disruption of Minar2 in mice leads to progressive hearing loss associated with alterations in the stereocilia of hair cells, the receptors of hearing, while hair cells remain intact until later in life. We present
MINAR2 as a gene working in the inner ear that is essential for hearing in humans and mice. Degeneration of sensory epithelium is a common consequence of hereditary deafness precluding genetic therapies. The preservation of hair cells in mutant mice at young ages makes MINAR2 a good candidate for intervention.
Discovery of deafness genes and elucidating their functions have substantially contributed to our understanding of hearing physiology and its pathologies. Here we report on DNA variants in
MINAR2, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness. Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show 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 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL). The c.393G > T variant is shown to disrupt a splice donor site. We show that
Minar2 is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis. Mice with loss of function of the Minar2 protein (
Minar2
tm1b/tm1b
) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age. We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL. Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies.
