Ophthalmological Findings in 6p Deletion Syndrome

Patients with a deletion at the terminal end of chromosome 6p can present with a variety of ophthalmological and systemic malformations. In this paper we present two patients with this chromosomal anomaly and similar anterior eye-segment abnormalities. We also give an overview of the literature on the ophthalmological findings in 6p deletion syndrome and compare our patients to those previously described in the literature. This syndrome should be considered in patients presenting with anterior segment dysgenesis and systemic abnormalities.     

A novel deletion downstream of the PAX6 gene identified in a Chinese family with congenital aniridia

Purpose: Congenital aniridia, a severe bilateral panocular visual disorder, is an autosomal dominantly inherited eye anomaly. Mutations in the paired box 6 gene (PAX6) have been shown to be responsible for congenital aniridia in most patients. The purpose of the present study was to report clinical features of a Chinese family with congenital aniridia and to screen novel genetic mutations for congenital aniridia.

Methods: All members of a three-generation family underwent comprehensive ophthalmic examination, and 8 of its 25 members were diagnosed with congenital aniridia. The proband was analyzed by exome sequencing and whole genome sequencing, and linkage analysis was performed for the family. The mutation was confirmed by direct DNA sequencing.

Results: Using Illumina’s Human Linkage-12 beadchip microarray (including 6090 SNPs) whole genome scan, the LOD score value showed that the interval on chromosome 11 between rs1389423 to rs910090 exhibited a strong linkage. A novel heterozygous 469 kb deletion mutation within the downstream region of PAX6 (chr11:31189937–31659379) was identified in all affected family members, but not in unaffected family members or 2000 ethnically matched controls.

Conclusion: A novel deletion mutation was identified within the PAX6 downstream region that results in congenital aniridia.     

A novel 5-bp deletion in Clarin 1 in a family with Usher syndrome

Background: To identify the genetic defect in a Lebanese family with two sibs diagnosed with Usher Syndrome.

Materials and Methods: Exome capture and sequencing were performed on DNA from one affected member using Agilent in solution bead capture, followed by Illumina sequencing.

Results: This analysis revealed the presence of a novel homozygous 5-bp deletion, in Clarin 1 (CLRN1), a known gene responsible for Usher syndrome type III. The deletion is inherited from both parents and segregates with the disease phenotype in the family. The 5-bp deletion, c.301_305delGTCAT, p.Val101SerfsX27, is predicted to result in a frameshift and protein truncation after 27 amino acids. Sequencing all the coding regions of the CLRN1 gene in the proband did not reveal any other mutation or variant.

Conclusion: Here we describe a novel deletion in CLRN1. Our data support previously reported intra familial variability in the clinical features of Usher syndrome type I and III.     

Features of KAT6B-related disorders in a patient with 10q22.1q22.3 deletion

Background: Blepharophimosis is a fixed reduction in the vertical distance between the upper and lower eyelids with short palpebral fissures. It is a rare facial malformation and is considered an important diagnostic feature in dysmorphic analysis. It is likely that many patients with blepharophimosis-mental retardation syndrome have submicroscopic chromosomal rearrangements, and the use of molecular karyotyping can narrow the known blepharophimosis-mental retardation–critical regions or clarify the effect of the haploinsufficiency of the involved genes on the phenotype.

Materials and methods: A female patient presented with bilateral blepharophimosis, ptosis, epicanthus inversus, telecanthus, low-set and small ears, other minor anomalies, hypotonia and psychomotor developmental delay. Metabolic investigations and array CGH analysis were performed. The results of molecular karyotyping were confirmed by real-time PCR analysis.

Results: Molecular karyotyping revealed a 5.2 Mb deletion in the 10q22.1q22.3 region. Real-time PCR analysis of the proband and her parents confirmed the deletion in the proband and revealed its de novo origin.

Conclusions: With ptosis, hypotonia, and developmental delay as the main diagnostic features of our patient, the effect of histone acetyltransferase-encoding KAT6B gene haploinsufficiency was suspected to have a significant role in determining the phenotype. Detailed clinical characterization of the patient provided additional information on the clinical manifestation of the 10q22 deletion.     

Distichiasis: An update on etiology,treatment and outcomes

Distichiasis, an extra row of eyelashes emerging from meibomian gland orifices, occurs due to the metaplastic transition of sebaceous glands into the pilosebaceous unit. It can present congenitally, such as in lymphedema distichiasis syndrome, or secondary to acquired conditions, such as cicatrizing conjunctivitis, trachoma. This review summarizes the etiology of distichiasis, its presentation, the evolution of various surgical techniques, and their outcomes in human and animal eyes. The published literature has focused on the different treatment modalities and their outcomes; the etiopathogenesis of this condition remains elusive. Truncating mutations (missense, frameshift, and nonsense) in the Forkhead family gene FOXC2 are involved in the distichiasis–lymphedema syndrome. The treatment options are no different for congenital versus acquired distichiasis, with no specific available algorithms. Acquired distichiasis in cicatrizing ocular surface diseases is difficult to manage, and existing treatment options offer success rates of 50%–60%. The outcomes of electroepilation or direct cryotherapy are not as good as surgical excision of distichiatic lashes after splitting the anterior and posterior lamella under direct visualization. The marginal tarsectomy with or without free tarsoconjunctival graft has shown good results in eyes with congenital and acquired distichiasis. The details of differences between normal and distichiatic lash, depth, or course of distichiatic eyelashes remain largely unknown. Studies exploring the distichiatic eyelash depth might improve the outcomes of blind procedures such as cryotherapy or radiofrequency-assisted epilation.     

玻璃体腔注射roscovitine对大鼠视网膜中Cdk5/p25活性和tau蛋白磷酸化的抑制作用

背景 视网膜色素变性(RP)与阿尔茨海默病有着共同的发病机制,细胞周期依赖性蛋白激酶(Cdk5)活性及其激活剂参与中枢神经系统的退行性病变.Cdk5抑制剂roscovitine可以抑制Cdk5/p25通路的活性,从而抑制细胞凋亡,但其对RP的影响尚不清楚. 目的 探讨玻璃体腔注射roscovitine对RCS大鼠视网膜组织中p35、p25和tau蛋白表达的影响.方法 12只RCS大鼠于出生后17d右眼玻璃体腔注射4 μlroscovitine作为实验眼,左眼未进行任何干预作为对照眼.分别于注射后8d(出生后25 d)和18d(出生后35 d)用过量麻醉法各处死6只大鼠并分离视网膜,Western blot法检测RCS大鼠视网膜组织中Cdk5、p35、p25蛋白的相对表达水平和tau蛋白磷酸化水平,采用分光光度仪(光谱法)测定大鼠视网膜组织340 nm处的吸光度(A)值,定量分析大鼠视网膜中Cdk5/p25激酶活性,采用配对t检验比较实验眼和对照眼的检测结果.结果 玻璃体腔注射后8d和18d,大鼠实验眼视网膜组织中p35蛋白的相对表达水平分别为1.186±0.019和1.069±0.019,明显低于对照眼的1.364±0.016和1.214±0.008,差异均有统计学意义(t=-6.294、-6.477,均P＜0.05);大鼠实验眼视网膜组织中p25蛋白的相对表达水平分别为0.312±0.009和0.269±0.018,明显低于对照眼的0.595±0.013和0.473±0.011,差异均有统计学意义(t=-36.508、-11.879,均P＜0.05);实验眼与对照眼间大鼠视网膜中Cdk5蛋白的相对表达水平差异均无统计学意义(t=0.213、-0.540,均P＞0.05);实验眼大鼠视网膜组织中tau蛋白磷酸化水平均低于对照眼,差异均有统计学意义(t=-9.854、-6.744,均P＜0.05).玻璃体腔注射后8d和18d,比色定量测定法测得大鼠实验眼视网膜中Cdk5/p25活性分别为(0.003 83±0.000 14)mol/(s·mg)和(0.00201±0.000 11)mol/(s·mg),明显低于对照眼的(0.005 47 ±0.000 27) mol/(s·mg)和(0.003 35±0.000 15) mol/(s·mg),差异均有统计学意义(t=-9.152,P=0.000;t=-9.248,P=0.000). 结论 玻璃体腔注射roscovitine可以在一定程度上抑制RCS大鼠视网膜组织中Cdk5/p25激酶活性及tau蛋白磷酸化水平.     

非干燥综合征干眼动物模型研究进展

干眼是一种会严重影响患者工作与生活的多因素疾病,至今发生机制未完全明确,尚无标准动物模型。非Sj9gren综合征干眼作为干眼的主要类型之一,需要进一步对其进行探究。随着干眼机制研究的深入,干眼动物模型也不断发展和完善。因此本文综述了包括药物、手术、外源性损害、行为模式、饮食结构改变等在内的非Sj9gren综合征干眼的动物造模方法,阐释不同模型的特点,分析存在的问题,并对今后研究提出展望和思考。     

Gastrointestinal microbiome and primary Sjögren's syndrome: a review of the literature and conclusions

The recognition of the profound impact of the human gastrointestinal microbiome (GM) on human autoimmune diseases has gradually increased thanks to deeper research efforts. As a systemic autoimmune disease, primary Sjögren''s syndrome (pSS) cannot be completely cured. Human studies have revealed that GM species and diversity are altered in patients with pSS compared with healthy individuals. Animal studies have provided possible mechanisms for the association between pSS and GM. The potential role of GM in pSS is exerted through several mechanisms. GM dysbiosis leads to increased intestinal permeability, which increases the risk of GM antigen exposure and activates specific autoreactive T lymphocytes via “molecular mimicry”. In addition, GM antigen exposure and intestinal immune tolerance loss caused by GM dysbiosis together induce chronic local gut mucosal inflammation, which deteriorates to systemic chronic non-specific inflammation with the circulation of pro-inflammatory lymphocytes and cytokines. These factors eventually activate autoreactive B lymphocytes and lead to pSS. If GM plays a key role in the pathogenesis of pSS, clarifying the underlying mechanisms will be helpful for the development of new therapies targeting GM for dry eye associated with pSS. This review summarizes the latest knowledge about the relationship between GM and pSS, with the aim of contributing to future research and to the development of new clinical applications.     

miR-124-3p靶向调控KLF6基因表达对H2O2诱导的人晶状体上皮细胞增殖和凋亡的影响

目的探讨微小RNA-124-3p(miR-124-3p)对H₂O₂诱导的人晶状体上皮细胞增殖及凋亡的影响及其靶向调控Krüppel样因子6(Krüppel like factor 6,KLF6)的机制。方法按HLE-B3细胞处理方式的不同,将其分为HLE-B3组、HLE-B3+H₂O₂组、HLE-B3+H₂O₂+miR-NC组、HLE-B3+H₂O₂+miR-124-3p组、HLE-B3+H₂O₂+si-NC组、HLE-B3+H₂O₂+si-KLF6组、miR-124-3p+pcDNA3.1组、miR-124-3p+pcDNA3.1-KLF6组。利用MTT实验检测各组HLE-B3细胞增殖活性,流式细胞仪检测各组HLE-B3细胞凋亡。双荧光素酶报告基因实验验证miR-124-3p与KLF6的靶向关系。Western blot检测...     

OTUD6B-AS1通过miR-21-5p对高糖诱导的ARPE-19细胞增殖、迁移的影响

目的　探讨高糖诱导的人视网膜色素上皮细胞（ARPE-19)中含有卵巢肿瘤结构域的6B反义RNA 1(OTUD6B-AS1)的功能及其作用机制。方法　取ARPE-19细胞,加入含30 mmol·L^-1葡萄糖的培养基培养,设为高糖组,另取ARPE-19细胞不做任何处理设为对照组。用Lipofectamine^TM 2000转染试剂分别将过表达空质粒（pcDNA-NC组）、OTUD6B-AS1过表达质粒（pcDNA-OTUD6B-AS1组）和OTUD6B-AS1过表达质粒＋miR-21-5p 模拟物（pcDNA-OTUD6B-AS1+miR-21-5p mimics组）转染进高糖诱导的ARPE-19细胞。实时荧光定量PCR（qRT-PCR）检测细胞中OTUD6B-AS1和miR-21-5p的表达;用CCK-8法检测各组细胞增殖能力;流式细胞术检测细胞凋亡情况;细胞划痕实验检测各组细胞迁移能力;荧光素酶报告基因实验验证OTUD6B-AS1与miR-21-5p的靶向关系。结果　与对照组比较,高糖组ARPE-19细胞中OTUD6B-AS1表达量显著降低、miR-21-5p表达量显著升高,差异均有统计学意义（均为P<0.05）。与对照组比较,高糖组细胞凋亡率显著升高,细胞增殖率和迁移率均显著降低,差异均有统计学意义(均为P<0.05）。与pcDNA-NC组比较,pcDNA-OTUD6B-AS1组中细胞增殖率和迁移率显著升高,细胞凋亡率显著降低,差异均有统计学意义(均为P<0.05）。双荧光素酶报告基因实验显示,OTUD6B-AS1可靶向miR-21-5p。与pcDNA-OTUD6B-AS1组比较,pcDNA-OTUD6B-AS1＋miR-21-5p mimics组细胞凋亡率显著升高,细胞增殖率和迁移率显著降低,差异均有统计学意义(均为P<0.05）。结论　OTUD6B-AS1可抑制高糖诱导的ARPE-19细胞凋亡,并促进细胞增殖和迁移,其作用机制与miR-21-5p有关。     

The diagnostic significance of Fourier‐domain optical coherence tomography in Sjögren syndrome,aqueous tear deficiency and lipid tear deficiency patients

Purpose: To determine the role of Fourier‐domain optical coherence tomography (FD‐OCT) in tear meniscus imaging and evaluate its diagnostic significance in Sjögren syndrome (SS), non‐Sjögren’s aqueous tear deficiency (ATD) and lipid tear deficiency (LTD) patients. Methods: Two hundred and thirty‐six dry eye patients and 174 healthy controls were enrolled in this study. All subjects were grouped as follows: group A (ATD), group B (LTD), group C (SS) and group D (normal controls). All subjects underwent dry eye questionnaire, FD‐OCT scanning, tear film break‐up time (BUT), corneal fluorescence staining and Schirmer I test (SIT). Tear meniscus height (TMH), tear meniscus depth (TMD) and tear meniscus cross‐sectional area (TMA) were measured using FD‐OCT (RTVue‐100). The area under the receiver operating characteristic curve and the cut‐off point were determined using a logistic regression model. Results: Mean TMH, TMD, TMA, BUT and SIT of dry eye patients were significantly lower than those of the controls (p < 0.05). Tear meniscus values were significantly decreased in patients with SS compared with ATD and LTD patients. Tear meniscus values were significantly correlated with clinical examination results in all groups. Accuracy of dry eye diagnosis by FD‐OCT is highest in patients with SS and lowest in LTD patients. The clinical diagnostic critical points were quite different between groups. Conclusions: Fourier‐domain optical coherence tomography could provide precise measurement of the tear meniscus with favourable repeatability. Diagnostic significance is more conspicuous in patients with SS. Tear meniscus measurement by FD‐OCT is expected to become a valuable technique in ATD dry eye screening and diagnosis.     

mTOR-siRNA转染人晶状体上皮细胞对PI3K/AKT/mTOR信号通路蛋白p70S6K及4EBP1表达的影响

目的　研究mTOR-siRNA转染人晶状体上皮细胞系B3(human lens epithelial line B3,HLEB3)后,对PI3K/AKT/mTOR信号通路蛋白p70S6K及4EBP1表达的影响,并与雷帕霉素的作用作对比。方法　HLEB3分为mTOR-siRNA组（培养基加入Lipo2000和mTOR-siRNA）、control-siRNA组（培养基加入Lipo2000和control-siRNA）、Lipo2000组（培养基加入Lipo2000）、雷帕霉素组（培养基加入雷帕霉素）和空白对照组,于转染24 h、48 h、72 h后观察各组细胞的形态和密度;Western blot法检测各时间点各组细胞p70S6K及4EBP1蛋白的表达情况。结果　mTOR-siRNA组随着转染时间延长,HLEB3细胞分布稀疏、形态不规则,部分细胞贴壁不良。转染24 h、48 h、72 h时,mTOR-siRNA组细胞密度均较其他四组低,差异均有统计学意义（均为P<0.05）。转染24 h后,各组细胞4EBP1蛋白表达差异无统计学意义（P>0.05）,但与空白对照组相比,mTOR-siRNA组及雷帕霉素组p70S6K蛋白表达均下降（均为P<0.05）;转染48 h、72 h后,与空白对照组相比,mTOR-siRNA组及雷帕霉素组4EBP1及P70S6K蛋白表达均下降（均为P<0.05）,而control-siRNA组、Lipo2000组4EBP1、P70S6K蛋白表达与空白对照组相比差异均无统计学意义（均为P>0.05）。结论　mTOR-siRNA及雷帕霉素均可影响HLEB3的增殖及生长活性,并抑制PI3K/AKT/mTOR信号通路蛋白p70S6K和4EBP1的表达,且mTOR-siRNA的早期作用较雷帕霉素强。     

The association of intraocular pressure with metabolic syndrome and its components: a Meta-analysis and systematic review

AIM: To perform a Meta-analysis to explore the correlation between metabolic syndrome and intraocular pressure (IOP). METHODS: We searched PubMed and Embase in November 2017 for studies discussing the relationship between metabolic syndrome components and IOP in patients. Pearson correlation coefficients, odds ratios and standardized betas were extracted from inclusive studies. Heterogeneity and publication bias were checked. RESULTS: Of 295 articles, 10 met inclusion criteria and provided sufficient data for Meta-analysis. Results showed a significant positive relation between metabolic syndrome and IOP (Z=0.47, 95%CI: 0.15-0.79, P=0.005). The five components [waist circumference, hypertriglyceridemia, high blood pressure, high fasting glucose and low high density lipoprotein (HDL)-cholesterol] of metabolic syndrome all showed positive correlation with IOP except the low HDL-cholesterol which had no statistical significance. The pooled Z was 0.08 (95%CI: 0.04-0.12), 0.16 (95%CI: 0.11-0.21), 0.16 (95%CI: 0.10-0.22), 0.30 (95%CI: 0.20-0.40) and 0.12 (95%CI: 0.08-0.16), respectively. Begg’s test and Egger’s test showed no evidence of significant publication bias of this Meta-analysis. CONCLUSION: Our findings suggest that metabolic syndrome and its components are significantly associated with IOP, besides the HDL-cholesterol. This association may be used to control IOP by intervening the occurrence of metabolic syndrome.     

The exfoliation syndrome: Source of the fibrillar material on the capsule

A clinical case of unilateral capsular exfoliation syndrome was observed in the previously traumatized eye of a 22-year-old man with a drawn-down pupil. The distribution of material corresponded to the folds of the inner surface of contiguous iris. The periphery of the lens appeared free of deposits. These findings contradict previous theories on the source of the fibrillar material from the lens epithelium and indicate that it is derived from the iris pigment epithelium and not from within the lens capsule, although there is no question but that the lens is involved in a similar process, the products of which probably do not reach the lens surface. The unilateral occurrence of the exfoliation syndrome in a traumatized eye of a 22-year-old man is unique and cannot be explained at this time.