Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis.

Background: The number of confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Japan are substantially lower in comparison to the US and UK, potentially due to the under-implementation of polymerase chain reaction (PCR) tests. Studies reported that more than half of the SARS-CoV-2 infections are asymptomatic, confirming the importance for conducting seroepidemiological studies. Although the seroepidemiological studies in Japan observed a reported prevalence of 0.10% in Tokyo, 0.17% in Osaka, and 0.03% in Miyagi, sampling bias was not considered. The study objective was to assess the seroprevalence of SARS-CoV-2 in a random sample of households in Utsunomiya City in Tochigi Prefecture, Greater Tokyo, Japan. Methods: We launched the Utsunomiya COVID-19 seROprevalence Neighborhood Association (U-CORONA) Study to assess the seroprevalence of COVID-19 in Utsunomiya City. The survey was conducted between 14 June 2020 and 5 July 2020, in between the first and second wave of the pandemic. Invitations enclosed with a questionnaire were sent to 2,290 people in 1,000 households randomly selected from Utsunomiya basic resident registry. Written informed consent was obtained from all participants. The level of IgG antibodies to SARS-CoV-2 was assessed by chemiluminescence immunoassay analysis. Results: Among 2,290 candidates, 753 returned the questionnaire and 742 received IgG tests (32.4 % participation rate). Of the 742 participants, 86.8% were 18 years or older, 52.6% were women, 71.1% were residing within 10 km from the test clinic, and 89.2% were living with another person. The age and sex distribution, distance to clinic and police district were similar with those of non-participants, while the proportion of single-person households was higher among non-participants than participants (16.2% vs. 10.8%). We confirmed three positive cases through quantitative antibody testing. No positive cases were found among the people who live in the same household as someone with positive. All cases were afebrile. The estimated unweighted and weighted prevalence of SARS-CoV-2 infection were 0.40% (95% confidence interval: 0.08-1.18%) and 1.23% (95% confidence interval: 0.17-2.28%), respectively. Conclusion: This study suggests the importance of detecting all cases using PCR or antigen testing, not only at a hospital, but also in areas where people assemble. Further prospective studies using this cohort are needed to monitor SARS-CoV-2 antibody levels.

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Eukaryotic genomes are organised into complex higher-order structures within the nucleus, and the three-dimensional arrangement of chromosomes is functionally important for global gene regulation. The existence of supernumerary chromosome 21 in Down syndrome may perturb the nuclear architecture at different levels, which is normally optimised to maintain the physiological balance of gene expression. However, it has not been clearly elucidated whether and how aberrant configuration of chromosomes affects gene activities. To investigate the effects of trisomy 21 on nuclear organisation and gene expression, we performed three-dimensional fluorescent imaging analysis of chromosome-edited human induced pluripotent stem cells (iPSCs), which enabled identification of the parental origin of the three copies of chromosome 21. We found that two copies of maternal chromosomes resulting from meiotic nondisjunction had a higher tendency to form an adjacent pair and were located relatively distant from the nuclear membrane, suggesting the conserved interaction between these homologous chromosomes. Transcriptional profiling of parental-origin-specific corrected disomy 21 iPSC lines indicated upregulated expression of the maternal alleles for a group of genes, which was accompanied by a fluctuating expression pattern. These results suggest the unique effects of a pair of maternal chromosomes in trisomy 21, which may contribute to the pathological phenotype.

The C-type natriuretic peptide (CNP)-natriuretic peptide receptor 2 (NPR2) signaling pathway plays an important role in chondrocyte development. Homozygous loss-of-function mutations of the NPR2 gene cause acromesomelic dysplasia, type Maroteaux (AMDM). The aim of this study was to identify and characterize NPR2 loss-of-function mutations in patients with AMDM. The NPR2 gene was sequenced in three Korean patients with AMDM and functional analysis of the mutated proteins was performed in vitro. Five novel NPR2 mutations were found in the three patients: two compound heterozygous mutations [c.1231T>C (Tyr411His) and c.2761C>T (Arg921X) in Patient 1 and c.1663A>T (Lys555X) and c.1711-1G>C (M571VfsX12) in Patient 3] and a homozygous mutation [c.2762G>A (Arg921Gln) in Patient 2]. Serum NT-proCNP concentration was significantly increased in each patient compared to control subjects. Cells transfected with the expression vector of each mutant except those found in Patient 3 showed a negligible or a markedly low cGMP response after treatment with CNP. HA-tagged wild-type (wt) and HA-mutant NPR2 were expressed at comparable levels: there were two bands of ∼130 and ∼120 kDa in wt and Arg921Gln, a single ∼120 kDa band in Tyr411His, and a single ∼110 kDa in the nonsense mutant. With respect to subcellular localization, Arg921Gln as well as wt-NPR2 reached the cell surface, whereas Tyr411His and Arg921X mutants did not. The Tyr411His and Arg921X NPR2 proteins were co-localized with an endoplasmic reticulum (ER) marker and failed to traffic from the ER to the Golgi apparatus. These results are consistent with deglycosylation experiments. Tyr411His and Arg921X NPR2 are complete loss-of-function mutations, whereas Arg921Gln behaves as a receptor for CNP with limited function.