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Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities.

功能获得MN1 截断变异引起可识别的颅面和脑异常综合征。

  • 影响因子:8.64
  • DOI:10.1016/j.ajhg.2019.11.011
  • 作者列表:"Miyake N","Takahashi H","Nakamura K","Isidor B","Hiraki Y","Koshimizu E","Shiina M","Sasaki K","Suzuki H","Abe R","Kimura Y","Akiyama T","Tomizawa SI","Hirose T","Hamanaka K","Miyatake S","Mitsuhashi S","Mizuguchi T","Takata A","Obo K","Kato M","Ogata K","Matsumoto N
  • 发表时间:2020-01-02
Abstract

:MN1 was originally identified as a tumor-suppressor gene. Knockout mouse studies have suggested that Mn1 is associated with craniofacial development. However, no MN1-related phenotypes have been established in humans. Here, we report on three individuals who have de novo MN1 variants that lead to a protein lacking the carboxyl (C) terminus and who presented with severe developmental delay, craniofacial abnormalities with specific facial features, and structural abnormalities in the brain. An in vitro study revealed that the deletion of the C-terminal region led to increased protein stability, an inhibitory effect on cell proliferation, and enhanced MN1 aggregation in nuclei compared to what occurred in the wild type, suggesting that a gain-of-function mechanism is involved in this disease. Considering that C-terminal deletion increases the fraction of intrinsically disordered regions of MN1, it is possible that altered phase separation could be involved in the mechanism underlying the disease. Our data indicate that MN1 participates in transcriptional regulation of target genes through interaction with the transcription factors PBX1, PKNOX1, and ZBTB24 and that mutant MN1 impairs the binding with ZBTB24 and RING1, which is an E3 ubiquitin ligase. On the basis of our findings, we propose the model that C-terminal deletion interferes with MN1's interaction molecules related to the ubiquitin-mediated proteasome pathway, including RING1, and increases the amount of the mutant protein; this increase leads to the dysregulation of MN1 target genes by inhibiting rapid MN1 protein turnover.

摘要

: MN1 最初被鉴定为肿瘤抑制基因。基因敲除小鼠研究提示Mn1 与颅面发育有关。然而,尚未在人类中建立MN1-related表型。在这里,我们报告了三个个体,他们具有导致缺乏羧基 (C) 末端的蛋白质的新生MN1 变体,并且表现出严重的发育迟缓,具有特定面部特征的颅面异常,大脑的结构异常。一项体外研究揭示了C端区域的缺失导致蛋白质稳定性增加,对细胞增殖的抑制作用,与野生型相比,MN1 在细胞核中的聚集增强,提示功能增加机制参与了这种疾病。考虑到C端缺失增加了MN1 内在无序区域的分数,改变的相分离可能参与了疾病的机制。我们的数据表明,MN1 通过与转录因子PBX1 、PKNOX1 和ZBTB24 相互作用参与靶基因的转录调控,突变MN1 损害了与ZBTB24 和RING1 的结合,它是一种E3 泛素连接酶。在我们发现的基础上,我们提出了C端缺失干扰MN1 与泛素介导的蛋白酶体途径相关的相互作用分子的模型,包括RING1,并增加突变蛋白的量; 这种增加通过抑制快速MN1 蛋白周转导致MN1 靶基因的失调。

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发表时间:2020-03-01
DOI:10.1007/s00787-019-01345-1
作者列表:["Peyroux E","Babinet MN","Cannarsa C","Madelaine C","Favre E","Demily C","Michael GA"]

METHODS::Impairments in social cognition have been frequently described in 22q11.2 deletion syndrome (22q11.2DS) and are thought to be a hallmark of difficulties in social interactions. The present study addresses aspects that are critical for everyday social cognitive functioning but have received little attention so far. Sixteen children with 22q11.2DS and 22 controls completed 1 task of facial expression recognition, 1 task of attribution of facial expressions to faceless characters involved in visually presented social interactions, and 1 task of attribution of facial expressions to characters involved in aurally presented dialogues. All three tasks have in common to involve processing of emotions. All participants also completed two tasks of attention and two tasks of visual spatial perception, and their parents completed some scales regarding behavioural problems of their children. Patients performed worse than controls in all three tasks of emotion processing, and even worse in the second and third tasks. However, they performed above chance level in all three tasks, and the results were independent of IQ, age and gender. The analysis of error patterns suggests that patients tend to coarsely categorize situations as either attractive or repulsive and also that they have difficulties in differentiating emotions that are associated with threats. An isolated association between the tasks of emotion and behaviour was found, showing that the more frequently patients with 22q11.2DS perceive happiness where there is not, the less they exhibit aggressive behaviour.

影响因子:0.95
发表时间:2020-02-01
DOI:10.1007/s11845-019-02039-y
作者列表:["Sheridan GA","Nagle M","Howells C","Gallagher O","Kiely PJ","O'Toole P","Kelly PM","Moore DP"]

METHODS:BACKGROUND:We describe the first radiographic clinic in the literature for DDH and how this novel clinic can significantly improve the efficiency and cost-effectiveness of service in a tertiary referral centre. AIMS:A radiographic clinic for the management of developmental dysplasia of the hip was introduced in 2017 in our institution. We performed a detailed cost analysis to assess the economic savings made with the introduction of this new clinic. We assessed the efficiency of the service by identifying how many unnecessary outpatient visits were prevented. We also assessed the difference in times from referral to review between the two clinics. METHODS:Analysis of the clinic activity in 2017 was possible as all data was collected prospectively by the DDH CNS and stored in our database. Cost analysis was performed, and the savings made per patient along with the financial benefit to our institution was recorded. RESULTS:The new radiographic clinic reduced the cost of reviewing one patient by €162.51 per patient. There was a 73% discharge rate from the clinic which prevented 251 unnecessary patient visits to the outpatient department over the course of the year. There was a significant 11-day reduction in waiting times between referral and review when comparing the radiographic to the conventional clinic (p < 0.05). CONCLUSIONS:A radiographic clinic for the management of developmental dysplasia of the hip has a significant effect on the efficiency and overall cost-effectiveness of service provision in a tertiary referral centre.

翻译标题与摘要 下载文献
影响因子:2.43
发表时间:2020-01-15
DOI:10.5435/JAAOS-D-16-00918
作者列表:["Grigoryan G","Korcek L","Eidelman M","Paley D","Nelson S"]

METHODS:INTRODUCTION:Triple pelvic osteotomy (TPO) involves periacetabular osteotomies of the ilium, ischium, and pubis to reorient the acetabulum. This operation is indicated in certain situations for the treatment of developmental dysplasia of the hip, dysplastic neuromuscular hips, and for containment of the femoral head in cases of Legg-Calvé-Perthes disease. METHODS:This retrospective cohort study compares radiographic outcomes of patients who underwent TPO using two different techniques and describes a novel single-incision direct lateral approach. TPO was performed on 22 patients by the senior author. The first 10 patients underwent TPO through a single-incision anterolateral approach. The last 12 patients underwent TPO using the direct lateral approach. Preoperative and postoperative pelvic radiographs were reviewed for each patient, and the migration index and center-edge angle were recorded. RESULTS:The migration index and center-edge angle were evaluated and were not found to be significantly different between the anterolateral and direct lateral groups. The direct lateral approach is described. CONCLUSION:The direct lateral approach for TPO is equivalent to the anterolateral approach on radiographic evaluation. Advantages of the direct lateral approach include direct visualization of the ischial osteotomy, effective mobilization of the acetabulum, and safety of the sciatic nerve.

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肌肉骨骼畸形方向

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