Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Identification of Odoribacter splanchnicus bacteremia using MALDI-TOF mass spectrometry and 16S rRNA sequencing: A case report.

Odoribacter splanchnicus was recently reclassified from the genus Bacteroides. We present the first case of Odoribacter splanchnicus bacteremia following appendicitis. The species was identified using MALDI-TOF mass spectrometry and later confirmed with 16S rRNA sequencing. The patient was successfully managed with surgery and antibiotic administration for two weeks.

The histone deacetylase inhibitor OBP-801 has in vitro/in vivo anti-neuroblastoma activity.

BACKGROUND: Patients with high-risk neuroblastoma have a poor prognosis; new therapeutic agents are therefore required. We investigated the antitumor effects of OBP-801, a novel histone deacetylase inhibitor, its underlying mechanism, and its potential as a therapeutic agent for patients with neuroblastoma. METHODS: The study included five human neuroblastoma cell lines: IMR32, GOTO, KP-N-RTBM, SK-N-AS, and SH-SY5Y. We investigated cell proliferation, cell cycle status, protein expression patterns, and apoptosis in neuroblastoma cells after OBP-801 treatment in vitro. Cell survival rate and cell cycle were analyzed using the WST-8 assay and flow cytometry, respectively. Apoptosis was detected using annexin V staining, and the expression of apoptosis-related proteins was investigated by western blotting. The antitumor activity of OBP-801 was examined in an in vivo xenograft mouse model. RESULTS: Dose-effect curve analysis showed that the mean half-maximal inhibitory concentration value was 5.5 ± 5.9 nM for the MYCN-amplified cell lines (IMR32, GOTO, and KP-N-RTBM) and 3.1 ± 0.7 nM for the MYCN-nonamplified cell lines (SK-N-AS and SH-SY5Y). OBP-801 inhibited cell proliferation and growth in all the cell lines. It induced G2/M phase arrest through the p21 (CDKN1A) pathway, increasing histone H3 levels and, subsequently, apoptosis in human neuroblastoma cells. OBP-801 suppressed the growth of neuroblastoma cells in the mouse xenograft model. CONCLUSIONS: Overall, OBP-801 induces M-phase arrest and apoptosis in neuroblastoma cells via mitotic catastrophe. Our results indicate that OBP-801 is a promising therapeutic agent with fewer adverse effects for patients with neuroblastoma.

Identification of a novel BOC-PLAG1 fusion gene in a case of lipoblastoma.

Lipoblastoma is a rare benign adipose tissue tumor that occurs mostly in infants and children. Histological diagnosis of lipoblastoma is sometimes difficult because it closely resembles other lipomatous tumors. The detection of PLAG1 gene rearrangement is useful for the diagnosis of lipoblastoma. Four PLAG1 fusion partner genes are known in lipoblastoma: HAS2 at 8q24.1, COL1A2 at 7q22, COL3A1 at 2q32, and RAB2A at 8q12. Herein, we describe a novel fusion gene in a case of lipoblastoma of left back origin. We identified a potential PLAG1 fusion partner using 5' rapid amplification of cDNA ends, and sequence analysis revealed the novel fusion gene, BOC-PLAG1. The BOC-PLAG1 fusion transcript consists of the first exon of the BOC gene fused to exon 2 or exon 3 of the PLAG1 gene. PLAG1 expression was found to be 35.7 ±â€¯2.1 times higher in the tumor specimen than in human adipocytes by qRT-PCR. As a result of the translocation, the constitutively active promoter of BOC leads to PLAG1 overexpression. The identification of the BOC-PLAG1 fusion gene will lead to more accurate diagnosis of lipoblastoma.

Mutations in the RAS pathway as potential precision medicine targets in treatment of rhabdomyosarcoma.

Precision medicine strategies for treating rhabdomyosarcoma (RMS), a childhood malignancy, have not been developed. We examined the effect of CH5126766, a potent selective dual RAF/MEK inhibitor, on RMS cell lines. Among the eleven cell lines studied, one NRAS and two HRAS mutated cell lines were detected. CH5126766 inhibited the proliferation and growth in all of the RAS-mutated RMS cell lines, while it induced G1 cell cycle arrest in two of them. G1 cell cycle arrest was accompanied by p21 up-regulation and RB dephosphorylation. CH5126766 also suppressed the in vivo growth of RAS-mutated RMS tumor, and the mice showed improved survival. Thus, our results demonstrate that CH5126766 is an effective RAF/MEK inhibitor in RAS-mutated RMS. This study not only shows that in RMS, mutations in the RAS pathway can be a target for precision medicine, but also demonstrates that the evaluation of the gene mutation status is important in childhood malignancies.

De novo IGF2 mutation on the paternal allele in a patient with Silver-Russell syndrome and ectrodactyly.

Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole-exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation- and methylation-sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.