👤 Hitoji Uchiyama

Crohn's disease (CD) is a chronic inflammatory bowel disease with unknown etiology. Inflammatory chemical mediators synthesized from arachidonic acid, an n-6 polyunsaturated fatty acid (PUFA), have been shown to activate CD. Additionally, n-3 PUFAs are metabolized by the same enzyme as n-6 PUFAs and known to inhibit the arachidonic acid cascade. Our previous study noted that the presence of erythrocyte membrane fatty acids is a characteristic finding in Japanese CD patients. It was thus speculated that To investigate the relationship of Using previously reported findings regarding The presence of the rs174538 mutation in The rs174538 mutation alters the fatty acid profile through strong linkage to the Show less

Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3. A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351-1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes. Exome sequencing identified a heterozygous CLN3 variant, NM₀₀₁₀₄₂₄₃₂.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178₁₈₀delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM₀₀₁₀₄₂₄₃₂.2:c.[295-2A > C]; [178₁₈₀delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989-2025) identified no hematologic abnormalities. This Japanese CLN3 patient developed visual impairment 7-8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients. Show less

Human single nucleotide variants in peroxisome proliferator-activated receptor-ɑ (PPARɑ) have been associated with beneficial metabolic phenotypes, yet their specific effects on metabolic gene expression are not well defined. Here, we developed a mouse model of a human PPARɑ variant encoding a substitution of valine for alanine at position 227 (V227A) to explore the role of this variant on systemic metabolism. Substitution with this variant in mice reduced plasma triglycerides, without altering body mass or liver lipid accumulation, consistent with phenotypes observed in human cohorts. Gene expression analysis revealed that the V227A variant enhances Ppara target gene expression in mouse liver, consistent with the effects of synthetic PPARɑ agonist treatment. Notably, V227A increased hepatic expression of Lpl, the predominant enzyme responsible for circulating triglyceride hydrolysis. Further characterization revealed that heart tissue from variant mice exhibited increased Lpl expression and triglyceride hydrolysis activity, suggesting that V227A enhances cardiac triglyceride clearance. These findings validate human observational studies and clarify the physiological impact of the V227A PPARɑ variant on plasma triglycerides. Show less

Complete endoscopic mucosal healing is defined as a Mayo endoscopic subscore of 0. Some patients diagnosed with a Mayo endoscopic subscore 0 may present with subsequent clinical relapse. Here, we aimed to demonstrate mucosal cytokine profile as a predictor of clinical relapse in ulcerative colitis patients with a Mayo endoscopic subscore of 0 as a marker of mucosal healing. We conducted prospective observational pilot study to examine the relationship between mucosal cytokine expression and subsequent relapse of UC patients diagnosed with a Mayo endoscopic subscore of 0. We enrolled 55 patients, and expression of cytokines tumor necrosis factor-α, interferon γ, interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin-12, interleukin-13, interleukin-15, interleukin-17A, interleukin-17F, interleukin-18, interleukin-21, interleukin-22, interleukin-23, interleukin-27, and interleukin-33 was measured by quantitative real-time PCR using rectal mucosa biopsy materials. Cytokine expression levels were compared between patients who relapsed between March 1, 2016, and March 30, 2020, of the study period and those who remained in remission. Ten cytokines, including interleukin-2, interleukin-4, interleukin-8, interleukin-10, interleukin-12, interleukin-15, interleukin-17A, interleukin-21, interleukin-23, and interleukin-33, were significantly elevated in patients with subsequent relapse compared with those who remained in remission. Interleukin-8 expression was the most useful predictor. In the rectal mucosa of ulcerative colitis patients with Mayo endoscopic subscore 0, levels of several cytokines were elevated in cases of subsequent relapse. Among these, interleukin-8 expression was the most useful for predicting relapse. Show less

Expression of intragenic exon rearrangements (IERs) has reportedly been detected in both normal and cancer cells. However, there have been few reports of occurrence of these rearrangements specific to neoplasms including malignant lymphoma. In this study, we detected IERs of ten genes (NBPF8, SOBP, AUTS2, RAB21, SPATA13, ABCC4, WDR7, PHLPP1, NFATC1 and MAGED1) in non-Hodgkin B cell lymphoma (B-NHL) cell line KPUM-UH1 using a high-resolution single nucleotide polymorphism array and reverse transcription polymerase chain reaction using reversely directed divergent primers within exons involved in genomic intragenic gains followed by sequencing analysis. Among them, the IERs involved in SOBP (6q21) exon 2 and 3 and AUTS2 (7q11.22) exon 2-4 were the molecular lesions specific to tumors and were frequently detected in B-NHL samples. These IERs constitute novel genetic alterations of B-NHL, which might be associated with tumorigenesis and be useful as genetic biological markers. Show less

Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rγ(-/-) (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American-British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia. Show less

Some patients with dilated cardiomyopathy (DCM) have mutations of the genes that encode sarcomeric or cytoskeletal proteins of cardiomyocytes, but the prevalence of these mutations in Japan remains unclear. A group of 99 unrelated adult patients with DCM (familial n=27, sporadic n=72) were screened for the following genes: cardiac beta-myosin heavy chain, cardiac myosin-binding protein C (MYBPC3), regulatory and essential myosin light chains, alpha cardiac actin, alpha tropomyosin, cardiac troponin T, cardiac troponin I, cardiac troponin C, dystrophin, and lamin A/C. A mutation (R820Q) in MYBPC3 was found in an aged patient. In addition, dystrophin mutations were identified in 3 male patients (2 with exon 45-48 deletion and 1 with exon 48-52 deletion). The prevalence of dystrophin mutations in male patients with DCM was 4.4% (3 of 68). No mutations involving amino acid changes were identified in the other genes. Although cases of adult patients with DCM caused by mutations of the genes encoding sarcomeric or cytoskeletal proteins of cardiomyocytes are infrequent in Japan, it may be advisable to screen older DCM patients for MYBPC3 mutations, and male patients with familial DCM for dystrophin mutations. Show less

Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessively inherited lysosomal storage disease involving a mutation in the CLN3 gene. The sequence of CLN3 was determined in 1995; however, the localization of the CLN3 gene product (Cln3p) was not confirmed. In this study, we investigated endogenous Cln3p using two peptide antibodies raised against two distinct epitopes of murine Cln3p. Identification of the liver 60 kDa protein as Cln3p was ascertained by amino acid sequence analysis using tandem mass spectrometry. Liver Cln3p was predominantly localized in the lysosomal membranes, not in endoplasmic reticulum (ER) or Golgi apparatus. As the tissue concentration of brain Cln3p was much lower than that of liver Cln3p, it could be detected only after purification from brain extract using anti-Cln3p IgG Sepharose. The apparent molecular masses of liver Cln3p and brain Cln3p were determined to be about 60 kDa and 55 kDa, respectively. Both brain and liver Cln3p were deglycosylated by PNGase F treatment to form polypeptides with almost the same molecular mass (45 kDa). However, they were not affected by Endo h treatment. In addition, it was also elucidated that the amino terminal region of Cln3p faces the cytosol. Show less

Body fat deposition was measured in overweight and non-overweight children using a bioelectrical impedance method, and its relationship with serum lipids and apolipoproteins was investigated in 90 overweight children (over 120% of their ideal weight) and 241 non-overweight children aged 10-15 years in Niigata Prefecture. The results were as follows. Overweight boys had significantly higher levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), atherogenic index (AI), RLP-cholesterol (RLP-C), apoA1, apoA2, apoB, apoC2, apoC3, apoE and the ratio of apoB to apoA1 than non-overweight boys. Overweight girls had significantly higher levels of TC, LDL-C, AI, remnant-like lopoprotein cholesterol (RLP-C), apoA2, apoB, apoC2, apoC3, apoE and the ratio of apoB to apoA1 than non-overweight girls. It has been reported that of all children studied 2.1% had higher levels of RLP-C than its upper limit known for adults (12 mg/dL). Of the overweight children in the present study, 4.4% had a high level of RLP-C whereas only 1.2% of non-overweight children had a high RLP-C level. No difference in the lipoprotein levels was found between overweight and non-overweight children. In both boys and girls, relative weight, body fat, skinfold thickness and body mass index (BMI) were correlated with the lipoprotein levels. Non-overweight boys whose body fat was over 20% had significantly higher levels of TC, LDL-C, apoA2, apoB, apoC2, apoE and apoB/A1 than those whose body fat was less than 20%. It was concluded that the measurement of body fat deposition, together with relative weight, was useful for detecting obesity and atherogenesity in Japanese school children. Show less