Mendelian susceptibility to mycobacterial diseases: state of the art

BackgroundMendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to infections caused by intracellular pathogens, such as mycobacteria, due to impaired IFN-γ immunity. To date, 18 different genes associated with MSMD have been reported.ObjectivesThis review describes recent discoveries, a 2020–2021 update, in MSMD through the introduction of three novel genetic disorders, namely, AR IFN-γ, T-bet, and ZNFX1 complete deficiency, as well as molecular mechanisms underlying multifocal osteomyelitis in patients with this condition.SourcesPubMed databases were searched for reports of MSMD since January 2020. Relevant articles and their references were screened.ContentThe review covers a general overview, known genes, classifications, symptoms, and treatments for MSMD. MSMD is classified into two groups: isolated MSMD and syndromic MSMD. Among the 18 genes responsible, 13 cause isolated MSMD, which is characterized by selective predisposition to one or more mycobacterial and related infections, and 8 cause syndromic MSMD, which involves the combination of the mycobacterial disease infectious phenotype with additional clinical phenotypes. Among the three genetic etiologies described herein, AR IFN-γ deficiency is classified as isolated MSMD, whereas AR T-bet and ZNFX1 deficiency are classified as syndromic MSMD. Multifocal osteomyelitis is a representative symptom of MSMD, and a high frequency of multifocal osteomyelitis is reported in MSMD patients due to impaired IFN-γ responses, such as with AD IFN-γR1, AD IFN-γR2, or AD STAT1 deficiency. Impaired inhibition of osteoclast differentiation and bone resorption owing to a poor response to IFN-γ has been shown to be in association with multifocal osteomyelitis in MSMD.ImplicationsOver the past decade, genetic dissection by next-generation sequencing techniques has contributed to the understanding of the molecular bases of human immunity to mycobacteria. However, genetic etiologies are lacking for half of MSMD cases. Further studies will be needed to elucidate the pathogenesis of MSMD.     

Assembly of HIV-1 Vif-Cul5 E3 ubiquitin ligase through a novel zinc-binding domain-stabilized hydrophobic interface in Vif

APOBEC3G (A3G) and related cytidine deaminases are potent inhibitors of retroviruses. HIV-1 Vif hijacks the cellular Cul5-E3 ubiquitin ligase to degrade APOBEC3 proteins and render them ineffective against these viruses. Here, we report that HIV-1 Vif is a novel zinc-binding protein containing an H-x(5)-C-x(17-18)-C-x(3-5)-H motif that is distinct from other recognized classes of zinc fingers. Zinc-binding stabilized a conserved hydrophobic interface within the HCCH motif that is critical for Vif-Cul5 E3 assembly and Vif function. An N-terminal region in the first Cullin repeat of Cul5, which is dispensable for adaptor ElonginC binding, was required for interaction with Vif. This region is the most divergent sequence between Cul2 and Cul5, a factor that may contribute to the selection of Cul5 and not Cul2 by Vif. This is the first example of a zinc-binding substrate receptor responsible for the assembly of a Cullin-RING ligase, representing a new target for antiviral development.     

Cytopathological and immunocytochemical findings of pancreatic anaplastic carcinoma with ZEB1 expression by means of touch imprint cytology

Pancreatic anaplastic carcinoma (PAC) is rare and has an aggressive clinical course. We report an autopsy case of PAC focusing on the cytopathological characteristics of the tumor and immunocytochemical staining for vimentin, E‐cadherin, and zinc finger E‐box binding homeobox 1 (ZEB1), which markers are associated with epithelial markers of epithelial‐mesenchymal transition (EMT). A 50‐year‐old woman presented to our hospital with a chief complaint of jaundice. A pancreatic head tumor and multiple liver nodules were detected on abdominal computed tomography. Biliary cytology under endoscopic retrograde cholangiopancreatography suggested ductal adenocarcinoma. Three months after admission, she died of multiorgan failure. At autopsy, touch imprint cytology using squash preparation of the pancreatic tumor identified two different cell types; numerous isolated malignant cells with large and pleomorphic nuclei and a few clusters showing irregularly overlapped nuclei and irregular contours within the necrotic background. Immunocytochemically, isolated cells were positive for vimentin and ZEB1, and negative for E‐cadherin. Conversely, clusters were negative for vimentin and ZEB1, and positive for E‐cadherin. Histologically, the tumor was composed of sarcomatous cells with small foci of adenocarcinoma, which were consistent with a diagnosis of PAC. Immunohistochemical staining of the adenocarcinoma and sarcomatous cells corresponded to those of the clusters and isolated malignant cells, respectively. Immunostaining of these EMT markers is useful to distinguish sarcomatous cells from adenocarcinoma and can contribute to the accurate diagnosis of pancreatic tumors with EMT.     

子宫内膜癌抑癌基因研究进展

子宫内膜癌是妇女常见的恶性肿瘤之一,发病率有逐年上升的趋势。随着分子生物学和免疫学的发展,关于子宫内膜癌分子水平的致癌机制研究日益深入,如癌基因、抑癌基因、DNA错配修复基因、雌激素代谢酶相关基因、甾体激素受体基因和细胞周期调控蛋白等。综述目前研究热点——抑癌基因的进展,为进一步探讨子宫内膜癌的发生发展、临床治疗及预后的判断提供重要依据。     

The zinc finger DNA-binding domain of K-RBP plays an important role in regulating Kaposi's sarcoma-associated herpesvirus RTA-mediated gene expression

K-RBP is a KRAB-containing zinc finger protein with multiple zinc finger motifs and represses Kaposi's sarcoma-associated herpesvirus (KSHV) transactivator RTA-mediated transactivation of several viral lytic gene promoters, including the ORF57 promoter. Whether K-RBP binds DNA through its zinc fingers and the role of zinc finger domain in repressing gene expression are unclear. Here we report that K-RBP binds DNA through its zinc finger domain and the target DNA sequences contain high GC content. Furthermore, K-RBP binds to KSHV ORF57 promoter, which contains a GC-rich motif. K-RBP suppresses the basal ORF57 promoter activity as well as RTA-mediated activation. The zinc finger domain of K-RBP is sufficient for the suppression of ORF57 promoter activation mediated by the viral transactivator RTA. Finally, we show that K-RBP inhibits RTA binding to ORF57 promoter. These findings suggest that the DNA-binding activity of K-RBP plays an important role in repressing viral promoter activity.     

环指感觉神经传导速度检测对诊断轻度腕管综合征的价值

目的：探讨环指感觉神经传导速度（SCV）测定对诊断轻度腕管综合征（CTS）的敏感性。方法：临床症状体征符合CTS,正中神经运动末端潜伏期正常的59例（62手）患者和50名（100手）年龄性别相匹配的健康对照参与本研究,采用顺向SCV测定法分别测定环指（指4）正中神经和尺神经SCV,指3正中神经SCV。结果：指4尺神经SCV〉46．6m／s,指4正中神经SCV〈44．6m／s,和（或）尺神经SCV与正中神经SCV差值〉8．1m／s（x＋2s）,符合CTS。正中神经SCV指3测定阳性率为70％,指4测定阳性率为82％,指4正中神经与尺神经SCV差值阳性率为96％。指4刺激可在29例（48手）患者腕部正中神经处记录到双峰电位,对照组未见。结论：比较指4正中神经和尺神经SCV的差值在鉴别轻度CTS方面是一个非常敏感的方法,腕部正中神经处记录到双峰电位是CTS确诊的明确指标。