A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the « molar tooth sign ». JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice‐site mutation in PDE6D, encoding a prenyl‐binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild‐type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl‐dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP‐bound ARL3, which acts as a cargo‐release factor for PDE6D‐bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl‐binding‐dependent trafficking in ciliopathies.     

A Robust Approach for Blind Detection of Balanced Chromosomal Rearrangements with Whole‐Genome Low‐Coverage Sequencing

Balanced chromosomal rearrangement (or balanced chromosome abnormality, BCA) is a common chromosomal structural variation. Next‐generation sequencing has been reported to detect BCA‐associated breakpoints with the aid of karyotyping. However, the complications associated with this approach and the requirement for cytogenetics information has limited its application. Here, we provide a whole‐genome low‐coverage sequencing approach to detect BCA events independent of knowing the affected regions and with low false positives. First, six samples containing BCAs were used to establish a detection protocol and assess the efficacy of different library construction approaches. By clustering anomalous read pairs and filtering out the false‐positive results with a control cohort and the concomitant mapping information, we could directly detect BCA events for each sample. Through optimizing the read depth, BCAs in all samples could be blindly detected with only 120 million read pairs per sample for data from a small‐insert library and 30 million per sample for data from nonsize‐selected mate‐pair library. This approach was further validated using another 13 samples that contained BCAs. Our approach advances the application of high‐throughput whole‐genome low‐coverage analysis for robust BCA detection—especially for clinical samples—without the need for karyotyping.     

颅脑有限元模型演化规律及其生物力学研究进展

交通事故中头颈部损伤因其较高的致命性,已成为最严重的损伤类型。有限元模型在创伤性脑损伤生物力学机理研究中得到日益广泛应用。回顾头颈部有限元模型的生物力学研究历史和现状,并阐述车辆碰撞交通事故中人体颅脑典型交通伤演化规律和生物力学研究进展,探索头颈部损伤安全防护的方法,以期为车辆碰撞事故中人体颅脑损伤生物力学研究和相应的汽车安全防护装置研制提供理论依据。     

髋关节声波诊断技术的建立及临床应用

发展一种非侵入性的声波诊断技术，通过评估髋关节声波传导特性，以反映髋关节的结构特征。所使用的声波分析仪包括3个系统：刺激系统，置于受试者的骶部中央提供振动和；声能转换系统为一对麦克风听诊器，安放在两侧股骨大转子和，以检拾穿过髋关节的声波信号，数据分析系统，为便携式装有双通道数字过滤程序可在1／3音节频带内进行声能测量的频率分析仪，对27名正常成人，20名正常学龄前儿童和40名正常新生儿分别进行了检测，结果显示：在200－315Hz的频率范围，两侧髋关节声波信号的相关性很高（CF＞0．9），声强差异很小（D＜3dB)，新生儿组，在更宽的频率范围（160－315Hz)两侧声波信号仍有很高的相关性（CF＞0．94），且声强差异更小（D＜2dB)，提示该声波诊断技术提供了一个有客观参数的评估髋关节声波传导特性的实用方法，为非侵入性显示骨关节结构特征及进一步研究和诊断髋关节疾患奠定了基础。     

Atypical blasts and bone marrow necrosis associated with near-triploid relapse of acute promyelocytic leukemia after arsenic trioxide treatment

The pathologic features of acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) are highly characteristic, which with few exceptions enable a firm diagnosis to be made on morphologic grounds. An APL patient in first relapse presented with large, bizarre circulating blasts and bone marrow necrosis 2 weeks after chemotherapy consolidation for an arsenic trioxide-induced remission. Although a morphologic diagnosis could not be reached, cytogenetic investigations showed a near-triploid clone with t(15;17), confirming APL in second relapse. This case showed that clonal evolution with additional karyotypic aberrations might alter the blast morphology and pathologic features in APL.     

Frequent allelic loss of 21q11.1 approximately q21.1 region in advanced stage oral squamous cell carcinoma

A fine mapping of loss of heterozygosity (LOH) was performed in oral squamous cell carcinoma (OSCC), using 12 markers on 21q11.1 approximately q21.1. We studied 43 resected primary invasive tumors and their paired normal tissues, concurrent dysplasia or carcinoma in situ in separate areas from 8 of the specimens, and 6 local recurrent carcinomas. LOH status was compared between lesions of different phases of progression within the same patient. A high frequency of LOH was observed for D21S1410, D21S120, and D21S1433 (60% each) in the primary lesions, constituting two interstitial deleted regions encompassing eight known genes. Cases showing LOH of D21S120 were significantly associated with advanced clinical stages (III and IV; P=0.02). Consistent allelic loss was observed in 64.2% of the informative cases between the precursor lesions and their corresponding invasive tumors, and in 59.5% of those between the primary lesions and their recurrent counterparts. Fewer than half of the different lesions within a given patient showed discordant allelic loss for tested markers. Our results suggest that 21q11.1 approximately q21.1 harbors tumor suppressor genes in OSCC. Genetic divergence may develop during tumor clone evolution.     

Sexual transmission of hepatitis B infection despite the presence of hepatitis B virus immunity in recipients of allogeneic bone marrow transplantation.

BACKGROUND: After hematopoietic cell transplantation (HCT), hepatitis due to hepatitis B virus (HBV) rarely occurred beyond the initial 12 months after transplantation. OBJECTIVES: We investigated the cause of "late" hepatitis due to HBV infection in two recipients after allogeneic HCT. STUDY DESIGN: Two male patients with acute myeloid leukemia and light chain myeloma, respectively, developed HBV-related hepatitis more than 2 years after HCT. All serum samples collected from the recipients, donors and their respective spouses were tested for HBV DNA by nested PCR, and if positive further quantified by Digene Hybrid Capture assay II. The HBV genotype was determined by PCR and sequencing. RESULTS: Genotypic analysis suggested that the cause of "late" hepatitis was due to acute HBV infection transmitted from their respective spouse. CONCLUSION: Our findings suggested that sexual precautions should be taken in these patients after HCT. Alternatively, or even additionally, active vaccination should be delivered to these patients once they have lost their HBV immunity.