Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice

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.

Hearing loss (HL) is one of the most common sensory deficits, affecting ∼1 in 500 newborns (1). Genetic factors are implicated in the majority of cases, with more than 80% of the inherited form exhibiting autosomal recessive transmission (2). No additional findings are present in over 70% of the cases, which are then classified as nonsyndromic HL (Hereditary Hearing Loss Homepage, https://hereditaryhearingloss.org/) (2, 3). Genetic testing for etiologic evaluation has become a standard of care in people with congenital or childhood-onset sensorineural HL, which is caused by pathologies of the inner ear and auditory nerve (4, 5). Recent studies have shown that screening all recognized HL genes for variants reveals underlying cause in about half of the affected individuals, leaving a significant portion of people with HL with an unknown etiology (6–9). In the era of emerging genetic therapies for HL, finding the etiology of HL in affected individuals has become a critical task. This is especially relevant for progressive HL, as genetic therapies may potentially stop progression while cochlear hair cells are still alive (10–12).MINAR2 (previously known as uncharacterized protein KIAA1024L and mouse gene A730017C20Rik) has recently been identified, and based on its structural similarity to MINAR1, named as major intrinsically disordered NOTCH2-associated receptor 2 or membrane integral NOTCH2-associated receptor 2 (13). A mutant mouse model of Minar2 showed motor deficits similar to those seen in Parkinson disease, with no information about hearing abnormalities (13). A Minar2 mutant mouse line, Minar2^tm1b, has also recently been reported to show no auditory brainstem responses at 14 wk old as part of a large HL screen (Mouse Genome Informatics [MGI]: 2442934) (11). Functional aspects of MINAR2 and consequences of its dysfunction in humans remain unknown.In this study, to better map the landscape of hereditary HL, we sought DNA variants underlying deafness in 13 affected individuals from four families. We identified three different MINAR2 variants in the families cosegregating with HL. We further showed that homozygous Minar2^tm1b mutant mice develop rapidly progressive HL associated with changes in outer hair cell stereocilia. Finally, via in vitro studies we demonstrated that MINAR2 suppresses NOTCH2, suggesting that notch signaling might play a role in pathogenesis.     

Combined tumour of aberrant cytokeratin expressing acral lentiginous melanoma and poroma: Diagnostic challenge

Combined tumours are uncommon and therefore these tumours may pose a diagnostic challenge. In the current case report, it is aimed to present the clinicopathological features of a combined tumour including melanoma with aberrant cytokeratin expression and poroma.     

Comparison of mitogen-induced proliferation in child and adult healthy groups by flow cytometry revealed similarities

Immunologic Research - The proliferation of antigen-specific lymphocyte clones, the initial step in acquired immunity, is vital for effector functions. Proliferation tests both in immunology...