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 (Minar2tm1b/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.

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer.

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two-stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10-6 , false discovery rate < 0.01). This locus containing seven single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55-2.54, P = 6.8 × 10-8 ). Further analysis of ChIP-sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis-regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene-set enrichment analysis. In vitro, RNAi-mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

Surgical treatment of acute acromioclavicular joint dislocations: hook plate versus minimally invasive reconstruction.

PURPOSE: This study was performed to compare the clinical results of a minimally invasive technique for acute acromioclavicular (AC) joint dislocation repair with the traditional hook plate fixation. METHODS: Forty-four patients with an acute (within 2 weeks after trauma) complete AC joint separation (35 male, nine female; median age 36.2 years, range 18-56) underwent surgical repair with either a minimally invasive AC joint repair or a conventional hook plate. Functional outcome was evaluated using the Constant-Murley Score (CMS), the TAFT score and the AC joint instability score (ACJI). Radiographic evaluation was performed with bilateral anterior-posterior (a.p.) stress and Alexander views. RESULTS: All patients were available after a median follow-up of 32 months (range 24-51). There were no significant differences in the mean CMS, Taft score and the ACJI between the two groups. The radiological assessment revealed no significant difference in the coracoclavicular distance. In both groups, a slight loss of reduction was observed. Periarticular ossification was seen in 11 patients of the minimally invasive AC joint repair and eight patients of the hook plate group but this did not affect the final outcome. Hook plates were removed after a median interval of 11.9 weeks (range 10-13). CONCLUSION: Good clinical results can be achieved with both minimally invasive AC joint repair and hook plate fixation. However, in the hook plate group a second operation is mandatory for plate removal. LEVEL OF EVIDENCE: III.

Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity.

OBJECTIVE: Obesity is a complex disorder and is linked to chronic diseases such as type 2 diabetes. Major intrinsically disordered NOTCH2-associated receptor2 (MINAR2) is an understudied protein with an unknown role in obesity and metabolism. The purpose of this study was to determine the impact of Minar2 on adipose tissues and obesity. METHOD: We generated Minar2 knockout (KO) mice and used various molecular, proteomic, biochemical, histopathology, and cell culture studies to determine the pathophysiological role of Minar2 in adipocytes. RESULTS: We demonstrated that the inactivation of Minar2 results in increased body fat with hypertrophic adipocytes. Minar2 KO mice on a high-fat diet develop obesity and impaired glucose tolerance and metabolism. Mechanistically, Minar2 interacts with Raptor, a specific and essential component of mammalian TOR complex 1 (mTORC1) and inhibits mTOR activation. mTOR is hyperactivated in the adipocytes deficient for Minar2 and over-expression of Minar2 in HEK-293 cells inhibited mTOR activation and phosphorylation of mTORC1 substrates, including S6 kinase, and 4E-BP1. CONCLUSION: Our findings identified Minar2 as a novel physiological negative regulator of mTORC1 with a key role in obesity and metabolic disorders. Impaired expression or activation of MINAR2 could lead to obesity and obesity-associated diseases.

[Operative treatment of acute acromioclavicular joint dislocation with anatomic reconstruction]. / Akut acromioclavicularis ízületi ficamok mutéti kezelése anatómiai rekonstrukcióval.

INTRODUCTION: The authors audited the outcomes of various surgical interventions employed to fix the dislocations of the acromioclavicular joint in their unit. This resulted in changing their method to treat this condition. OBJECTIVE: Finding a technique that results in the best functional stability of the injured joint while preserving its physiological function. METHOD: In this particular area of traumatology, there is still uncertainty of the ideal way to provide the best outcome in terms of stability and function. From the currently known techniques, the authors have chosen the Minimally INvasive Acromioclavicular Joint Reconstruction (MINAR) method to be introduced in their unit. Its advantage is that it provides good stability combined with fast rehabilitation with a minimally invasive intervention. Furthermore, it is safe and easy to learn and master. It is also to be pointed out that it restores not only the stability but also the physiological functionality of the damaged joint. The authors carried out this type of operation first in 2012. They promoted the technique first in Hungary and became a 'reference centre' in the country. The authors will detail the method itself, both its indications and contraindications as well as the stages of the postoperative rehabilitation. RESULTS: The authors scrutinized their results with imaging and 7 years of retrospective analysis with Constant and DASH scores. These were all in support of their choice of the MINAR method. DISCUSSION: The authors concluded results congruent with international studies and recommendations. Additional analysis deducted aspects of the technique that could lead to further improvement in outcomes and highlighted areas for future study. CONCLUSION: In line with the recommendation of the European Shoulder Associates, the author's recommendation is that the MINAR technique should be the first choice of intervention for dislocations of the acromioclavicular joint. Orv Hetil. 2022; 163(50): 1992-1999.

Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice.

Parkinson's disease is the second most common human neurodegenerative disease. Motor control impairment represents a key clinical hallmark and primary clinical symptom of the disease, which is further characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of α-synuclein aggregations. We have identified major intrinsically disordered NOTCH2-associated receptor 2 encoded by KIAA1024L, a previously uncharacterized protein that is highly conserved in humans and other species. In this study, we demonstrate that major intrinsically disordered NOTCH2-associated receptor 2 expression is significantly down-regulated in the frontal lobe brain of patients with Lewy body dementia. Major intrinsically disordered NOTCH2-associated receptor 2 is predominantly expressed in brain tissue and is particularly prominent in the midbrain. Major intrinsically disordered NOTCH2-associated receptor 2 interacts with neurogenic locus notch homologue protein 2 and is localized at the endoplasmic reticulum compartments. We generated major intrinsically disordered NOTCH2-associated receptor 2 knockout mouse and demonstrated that the loss of major intrinsically disordered NOTCH2-associated receptor 2 in mouse results in severe motor deficits such as rigidity and bradykinesia, gait abnormalities, reduced spontaneous locomotor and exploratory behaviour, symptoms that are highly similar to those observed in human Parkinson's spectrum disorders. Analysis of the major intrinsically disordered NOTCH2-associated receptor 2 knockout mice brain revealed significant anomalies in neuronal function and appearance including the loss of tyrosine hydroxylase-positive neurons in the pars compacta, which was accompanied by an up-regulation in α-synuclein protein expression. Taken together, these data demonstrate a previously unknown function for major intrinsically disordered NOTCH2-associated receptor 2 in the pathogenesis of Parkinson's spectrum disorders.

Minimally Invasive AC Joint Reconstruction System (MINAR®) in Modified Triple-Button Technique for the Treatment of Acute AC Joint Dislocation.

Acute acromioclavicular (AC) joint dislocation is a frequent sports injury with more than 100 different operation methods described. A total of 65 patients with an acute AC joint dislocation were treated with the modified MINAR® system between 2009 and 2013. Clinical outcome, horizontal and vertical instability, as well as concomitant intraarticular injuries were assessed. We used Zanca, stress and axial X-rays for radiological assessment. A Constant score of 95 (±8.8), University of California Los Angeles Shoulder score (UCLA) of 31 (±4.9), Disabilities of Arm, Shoulder and Hand (DASH) of 9.1 (±14.3), and Visual Analogue Scale (VAS) of 0.9 (±0.126) was found. A total of 30 patients (59%) had no signs of reduction loss, nine patients (18%) a slight loss, 11 patients (22%) a partial loss, and one patient (2%) a total loss. No significant influence on the clinical scores could be shown. The postoperative coracoclavicular (CC) distance negatively affected the Constant (p = 0.007) and UCLA scores (p = 0.035). A longer time interval to surgery had a negative influence on all scores (p ≤ 0.001). We could not find any signs of persistent horizontal instability or intraarticular injuries at follow-up. The MINAR® system promises satisfactory functional and radiological results. When setting the correct indication, patients benefit from an early operation. No persisting horizontal instability was observed following suturing of the AC capsule and the delta fascia.

Open reduction and fixation of displaced lateral clavicle fractures using the Minimally Invasive Acromioclavicular Joint Reconstruction (MINAR®) technique: a case series review.

BACKGROUND: Lateral end of clavicle fractures can be a challenge, with a 20% to 30% non-union rate if treated non-operatively. Several operative options exist, each having their own merits and some having potential disadvantages. The Minimally Invasive Acromioclavicular Joint Reconstruction (MINAR®) (Storz, Tutlingen, Germany) set uses an Orthocord (Depuy Synthes Mitek, Leeds, UK) suture and two Flip Tacks (Storz) via a transclavicular-coracoid approach to reconstruct the coracoclavicular ligaments. METHODS: Referrals were made to two senior surgeons at separate institutions regarding Robinson Type 3 fractures of the lateral end of the clavicle. All patients were treated with MINAR implant via a minimally invasive approach. Two-year follow-up was obtained using the Oxford Shoulder Score (OSS) and the Quick DASH (Disability of the Arm Shoulder and Hand) score. RESULTS: Sixteen cases of acute fractures of the lateral end of the clavicle were included in this series. At final follow-up, the mean OSS was 44.75 (range 35 to 48) and the median Quick DASH score was 2.3 (range 0 to 35.9). Fifteen patients achieved bony union (one asymptomatic non-union) and there were no complications or re-operations. CONCLUSIONS: The MINAR is reproducible and safe when treating lateral end of clavicle fractures. We consider that, over the short- to mid-term, it achieves results equivalent to those for other implants.

Minimally Invasive Coracoclavicular Ligament Reconstruction With a Flip-Button Technique (MINAR): Clinical and Radiological Midterm Results.

BACKGROUND: Acromioclavicular (AC) joint dislocation is a frequent injury in sports. HYPOTHESIS: A minimally invasive flip-button technique, MINAR (minimally invasive acromioclavicular joint reconstruction), will achieve good clinical and radiographic results in the surgical treatment of high-grade AC joint dislocations. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: In this study, 96 patients with AC joint dislocation grades III through V and minimally invasive flip-button repair were identified. Radiographic assessment was performed by use of the Alexander view and by anteroposterior stress radiograph. Clinical outcomes were assessed with the Constant and Taft scores. Factors that influenced outcomes, such as age, time from trauma to surgery, and degree of dislocation, were evaluated. RESULTS: Of the 96 patients, 83 (86.4%; 3 women and 80 men) were able to participate in clinical and radiographic follow-up. The average age of the participants was 39 years (range, 17-80 years). At a mean follow-up of 39 months (range, 12-78 months), clinical assessment revealed excellent results with a mean Constant score of 94.7 (range, 61-100). Clinical and radiological assessment using the Taft score also showed excellent results, with a mean score of 10.8 (range, 3-12). The mean time period from trauma to surgery was 6 days (range, 0-22 days), and mean duration of surgery was 48 minutes (range, 24-98 minutes). Nine patients (10.8%) underwent revision surgery due to recurrent dislocation (n = 8) or wound infection (n = 1). Radiological assessment showed that 18 patients had sustained a loss of reduction defined as subluxation of 50% of the clavicle shaft width in the vertical plane. However, there was no significant correlation (P = .254) with clinical outcome. Patient age was a relevant factor influencing outcome, as significantly higher outcome values were detected for younger patients (P = .024). No significant influence was shown for the time period from trauma to surgery (P = .336) or degree of dislocation after trauma (P = .987). CONCLUSION: The MINAR technique is a safe procedure and achieves good to excellent clinical and radiographic results in the surgical treatment of high-grade AC joint dislocations. Despite the simplicity of this technique, the surgeon has to overcome the learning curve to minimize the risk of recurrent dislocation.