Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence

<p>Abstract</p> <p>Background</p> <p>Anderson's Disease (AD)/Chylomicron Retention Disease (CMRD) is a rare hereditary hypocholesterolemic disorder characterized by a malabsorption syndrome with steatorrhea, failure to thrive and the absence of chylomicrons and apolipoprotein B48 post-prandially. All patients studied to date exhibit a mutation in the <it>SAR1B </it>gene, which codes for an essential component of the vesicular coat protein complex II (COPII) necessary for endoplasmic reticulum to Golgi transport. We describe here a patient with AD/CMRD, a normal <it>SAR1B </it>gene protein coding sequence and maternal uniparental disomy of chromosome 7 (matUPD7).</p> <p>Methods and Results</p> <p>The patient, one of two siblings of a Japanese family, had diarrhea and steatorrhea beginning at five months of age. There was a white duodenal mucosa upon endoscopy. Light and electron microscopy showed that the intestinal villi were normal but that they had lipid laden enterocytes containing accumulations of lipid droplets in the cytoplasm and lipoprotein-size particles in membrane bound structures. Although there were decreased amounts in plasma of total- and low-density lipoprotein cholesterol, apolipoproteins AI and B and vitamin E levels, the triglycerides were normal, typical of AD/CMRD. The presence of low density lipoproteins and apolipoprotein B in the plasma, although in decreased amounts, ruled out abetalipoproteinemia. The parents were asymptomatic with normal plasma cholesterol levels suggesting a recessive disorder and ruling out familial hypobetalipoproteinemia. Sequencing of genomic DNA showed that the 8 exons of the <it>SAR1B </it>gene were normal. Whole genome SNP analysis and karyotyping revealed matUPD7 with a normal karyotype. In contrast to other cases of AD/CMRD which have shown catch-up growth following vitamin supplementation and a fat restricted diet, our patient exhibits continued growth delay and other aspects of the matUPD7 and Silver-Russell Syndrome phenotypes.</p> <p>Conclusions</p> <p>This patient with AD/CMRD has a normal <it>SAR1B </it>gene protein coding sequence which suggests that factors other than the SAR1B protein may be crucial for chylomicron secretion. Further, this patient exhibits matUPD7 with regions of homozygosity which might be useful for elucidating the molecular basis of the defect(s) in this individual. The results provide novel insights into the relation between phenotype and genotype in these diseases and for the mechanisms of secretion in the intestine.</p

Left atrial extension of metastatic lung tumor via pulmonary vein: report on the first case of Ewing sarcoma

Extension of metastatic lung tumors into the left atrium via pulmonary veins is rare. Here, we report the first case of Ewing sarcoma exhibiting such extension. A 31-year-old man with pulmonary metastasis from Ewing sarcoma presented with a mass in the left lung, extending to the left atrium through the left inferior pulmonary vein. As the patient was considered to be at risk of tumor embolism, the mass was excised surgically

Interleukin-6 Expression on the Biliary Epithelia During Inflammation-Associated Biliary Carcinogenesis in Bilioenterostomized Hamsters.

BACKGROUND: Chronic inflammatory conditions of the biliary tree strongly predispose patients to biliary carcinoma. The aim of this study was to evaluate the role of interleukin-6 (IL-6) expression during biliary carcinogenesis in bilioenterostomized hamsters. MATERIALS AND METHODS: Syrian hamsters were subjected to either a choledochoduodenostomy (CD, n=11) or a simple laparotomy (SL, n=10) and then received N-nitrosobis(2-oxopropyl)amine (BOP) treatment. The animals were sacrificed 20 wk after surgery and the development of biliary carcinoma, the presence and degree of cholangitis, and IL-6 expression on the biliary epithelia were examined histologically. RESULTS: In the CD group, eight hamsters (73%) demonstrated persistent cholangitis and six (55%) of them developed intrahepatic biliary carcinoma, while no hamster without cholangitis showed any biliary carcinoma. In the SL group, cholangitis was recognized in four hamsters (40%) and no development of biliary carcinoma was identified. A significantly high incidence of tumor development (P=0.024) and a close correlation between the presence of cholangitis and the occurrence of biliary carcinoma (P =0.013) were thus evident in the CD group. Moreover, the degree of cholangitis was significantly higher in the CD hamsters (P=0.041) and an IL-6 overexpression was identified in five hamsters that had undergone a CD, with a scattered expression on the intra- and extrahepatic biliary epithelia. Despite the fact that the induced biliary carcinomas showed a multicentric occurrence in the liver, these tumors originated from within the restricted area where IL-6 was expressed. CONCLUSIONS: A deregulated IL-6 overexpression on the biliary epithelia may therefore be involved in inflammation-associated biliary carcinogenesis in hamsters that have undergone a bilioenterostomy

Collaborative Action of Brca1 and CtIP in Elimination of Covalent Modifications from Double-Strand Breaks to Facilitate Subsequent Break Repair

Topoisomerase inhibitors such as camptothecin and etoposide are used as anti-cancer drugs and induce double-strand breaks (DSBs) in genomic DNA in cycling cells. These DSBs are often covalently bound with polypeptides at the 3′ and 5′ ends. Such modifications must be eliminated before DSB repair can take place, but it remains elusive which nucleases are involved in this process. Previous studies show that CtIP plays a critical role in the generation of 3′ single-strand overhang at “clean” DSBs, thus initiating homologous recombination (HR)–dependent DSB repair. To analyze the function of CtIP in detail, we conditionally disrupted the CtIP gene in the chicken DT40 cell line. We found that CtIP is essential for cellular proliferation as well as for the formation of 3′ single-strand overhang, similar to what is observed in DT40 cells deficient in the Mre11/Rad50/Nbs1 complex. We also generated DT40 cell line harboring CtIP with an alanine substitution at residue Ser332, which is required for interaction with BRCA1. Although the resulting CtIPS332A/−/− cells exhibited accumulation of RPA and Rad51 upon DNA damage, and were proficient in HR, they showed a marked hypersensitivity to camptothecin and etoposide in comparison with CtIP+/−/− cells. Finally, CtIPS332A/−/−BRCA1−/− and CtIP+/−/−BRCA1−/− showed similar sensitivities to these reagents. Taken together, our data indicate that, in addition to its function in HR, CtIP plays a role in cellular tolerance to topoisomerase inhibitors. We propose that the BRCA1-CtIP complex plays a role in the nuclease-mediated elimination of oligonucleotides covalently bound to polypeptides from DSBs, thereby facilitating subsequent DSB repair

High-resolution seismic reflection survey across the Western Boundary Fault Zone of the Nagano Basin, Central Japan: Data acquisition and processing

The Western Boundary Fault Zone of the Nagano Basin borders the eastern margin of Northern Fossa Magna, which has undergone strong horizontal shortening since Pliocene. The Western Boundary Fault Zone of the Nagano Basin is considered to be a back thrust that developed on the hanging wall side of the Itoigawa-Shizuoka Tectonic Line. To reveal the subsurface structure of the Western Boundary Fault Zone of the Nagano Basin, we carried out a high-resolution seismic reflection survey along the Saigawa River, southern Nagano City. The source used in this survey was a mini-vibrator (T-15000). Source and receiver spacing was 10 m. 180 channels of geophone arrays were used to record each shot. The seismic section obtained after careful data processing shows fairly flat Quaternary basin fillings in the eastern part of the seismic line. The Quaternary basin fillings are interpreted to be in west-dipping fault contact with west-dipping Neogene strata underlying the Saigawa Hills

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

High-resolution seismic reflection profiling across the Shiraiwa fault, eastern margin of the Yokote basin fault zone, northeast Japan : data acquisition and processing

The eastern margin of the Yokote basin fault zone extends about 56km at the western foot of the Ou Backbone Range, northeast Japan. The Rikuu earthquake (M=7.2) occurred in the Ou Backbone Range (Mahiru Range) on 31st August, 1896. Associated with this earthquake, four thrust faults-Obonai, Shiraiwa, Ota, and Senya fault3 appeared on the surface of the western foot of the Mahiru Range. These faults were highly sinuous with numerous gaps and en echelon steps. We conducted a high-resolution seismic reflection profiling survey across the Shiraiwa fault. The obtained seismic reflection data were processed by conventional common mid-point methods, post-stack migration, and depth conversion. The subsurface structure across the Shraiwa fault is characterized by branched low-angle reverse faults and conjugate back-thrust. The emergent thrust associated with the 1896 earthquake is regarded to be a subsidiary reverse fault