Novel c.2216T > C (p.I739T) Mutation in Exon 13 and c.1481T > A (p.L494X) Mutation in Exon 8 of MUT Gene in a Female with Methylmalonic Acidemia

We report herein a 1.5-year-old girl with methylmalonic acidemia (MMA) in whom two missense mutations were found: a novel I739T mutation located in exon 13 and the L494X mutation in exon 8. The results of organic acid test showed a pronounced increase in methylmalonate excretion with increased methylcitrate and 3-OH-propionate excretion, leading to a diagnosis of MMA, and Vitamin B12 administration was started. Analysis of the mut gene confirmed a T-to-A substitution at nucleotide position 1481 in exon 8 and a T-to-C substitution at nucleotide position 2216 in exon 13, leading to the amino acid isoleucine at position 739 being changed to threonine, resulting in c.2216T > C (p.I739T). The patient has now been on high-dose oral administration of Vitamin B12 and carnitine therapy (900 mg of levocarnitine chloride) for 5 years without experiencing further attacks, and her cognitive and motor development is normal. Further tests on residual enzyme activity, as well as experience with more cases, may shed light on the relationship between gene mutations and phenotypes in MMA

Chromosome Analysis Using Spectral Karyotyping (SKY)

Spectral karyotyping is a novel technique for chromosome analysis that has been developed based on the approach of the fluorescence in situ hybridization technique. Spectral karyotyping makes it feasible to diagnose a variety of diseases, because of its technology in painting each of the 24 human chromosomes with different colors. In recent years, it has become possible to adopt the usage of spectral karyotyping for research in general clinical practice, and its usability has attracted particular attention in the diagnosis of different diseases. In this review, we will explain the principle of the spectral karyotyping, as well as its specificity and limitation in detecting the genetic defects within clinical application by presenting two case reports

Treatment Strategy for Pediatric Patients with Nephrotic Syndrome with Microscopic Hematuria at the Onset: A Retrospective Study of the Need for Kidney Biopsy

Nephrotic syndrome (NS) in children responds well to steroid therapy, therefore kidney biopsy before treatment is often avoided. However, the indications for kidney biopsy in children with NS with microscopic hematuria are controversial. In the present study, the indications for pretreatment kidney biopsy at the onset of pediatric patients with NS with microscopic hematuria were evaluated. Clinicopathologic correlations were retrospectively examined from patients enrolled in a database from January 2005 to December 2018. Fifty-nine pediatric patients with NS were enrolled. Among them, 6 with hypocomplementemia, gross hematuria, or onset at less than 1 year of age were excluded. Of the 53 enrolled patients, 38 without hematuria were assigned to Group A, and 15 patients with microscopic hematuria comprised Group B. There was a significant difference in the renal biopsy rate between Group A (n = 19, 50%) and Group B (n = 13, 87%) (P = 0.01). Two patients in Group B avoided biopsy. Pathology results for patients in Group B included 4 patients with minimal change disease, 2 with focal segmental glomerulosclerosis, 6 with mesangial proliferative glomerulonephritis (non-IgA), and 1 with membranous lupus nephritis (LN). The first three are commonly found in pediatric patients with NS, and all are treated with steroid therapy. LN could be diagnosed by kidney biopsy at the time of steroid resistance. LN presenting with nephrotic syndrome is also treated with steroids. Thus, the treatment strategy would not have changed even if the kidney biopsy had been performed before treatment. These results suggest that renal biopsy is not always mandatory during the initial stage for pediatric patients with NS with microscopic hematuria.journal articl

P-450; Structure, Function, and Regulation

開始ページ、終了ページ: 冊子体のページ付

The two eIF4A helicases in Trypanosoma brucei are functionally distinct

Protozoan parasites belonging to the family Trypanosomatidae are characterized by an unusual pathway for the production of mRNAs via polycistronic transcription and trans-splicing of a 5' capped mini-exon which is linked to the 3' cleavage and polyadenylation of the upstream transcript. However, little is known of the mechanism of protein synthesis in these organisms, despite their importance as agents of a number of human diseases. Here we have investigated the role of two Trypanosoma brucei homologues of the translation initiation factor eIF4A (in the light of subsequent experiments these were named as TbEIF4AI and TbEIF4AIII). eIF4A, a DEAD-box RNA helicase, is a subunit of the translation initiation complex eIF4F which binds to the cap structure of eukaryotic mRNA and recruits the small ribosomal subunit. TbEIF4AI is a very abundant predominantly cytoplasmic protein (over 1 x 10(5) molecules/cell) and depletion to similar to 10% of normal levels through RNA interference dramatically reduces protein synthesis one cell cycle following double-stranded RNA induction and stops cell proliferation. In contrast, TbEIF4AIII is a nuclear, moderately expressed protein (similar to 1-2 x 10(4) molecules/cell), and its depletion stops cellular proliferation after approximately four cell cycles. Ectopic expression of a dominant negative mutant of TbEIF4AI, but not of TbEIF4AIII, induced a slow growth phenotype in transfected cells. Overall, our results suggest that only TbEIF4AI is involved in protein synthesis while the properties and sequence of TbEIF4AIII indicate that it may be the orthologue of eIF4AIII, a component of the exon junction complex in mammalian cells

Clinically Mild Encephalopathy with a Reversible Splenial Lesion Accompanying Mumps Virus Infection：a 5-Year-Old Girl Report

Aseptic meningitis is known as a mumps complication. However, there are few cases of clinically mild encephalopathy with a reversible splenial lesion（MERS） associated with mumps infection. We report a MERS related to mumps infection in a girl. In the early clinical course, repeating convulsion and consciousness disturbance with hallucination were recognized. Initially, we suspected aseptic meningitis due to mumps, because of her swollen right parotid gland. Cerebrospinal fluid test was performed, but the result was normal. After that, diffusion weighted image of magnetic resonance imaging was added and abnormal signal intensity was recognized in the corpus callosum, so she was diagnosed as MERS. Treatment was performed with steroid pulse therapy and patients was discharged without neurologic sequelae. We need to pay attention to MERS as complication although rare in a mumps infection

山下先生を偲ぶ

山下龍二先生追悼文 (Memorial Writings dedicated to the late Professor Ryuji Yamashita)departmental bulletin pape

Neural RNA-binding protein Musashi1 inhibits translation initiation by competing with eIF4G for PABP

Musashi1 (Msi1) is an RNA-binding protein that is highly expressed in neural stem cells. We previously reported that Msi1 contributes to the maintenance of the immature state and self-renewal activity of neural stem cells through translational repression of m-Numb. However, its translation repression mechanism has remained unclear. Here, we identify poly(A) binding protein (PABP) as an Msi1-binding protein, and find Msi1 competes with eIF4G for PABP binding. This competition inhibits translation initiation of Msi1's target mRNA. Indeed, deletion of the PABP-interacting domain in Msi1 abolishes its function. We demonstrate that Msi1 inhibits the assembly of the 80S, but not the 48S, ribosome complex. Consistent with these conclusions, Msi1 colocalizes with PABP and is recruited into stress granules, which contain the stalled preinitiation complex. However, Msi1 with mutations in two RNA recognition motifs fails to accumulate into stress granules. These results provide insight into the mechanism by which sequence-specific translational repression occurs in stem cells through the control of translation initiation