Ryuichi Kuromaru

Identification of a novel type 1 diabetes susceptibility gene, T-bet

The gene encoding interferon (IFN)-γ, IFNG, is known as one of the candidate susceptibility genes for type 1 diabetes. In addition, cytokines, including IFN-γ, play important roles in the pathogenesis of type 1 diabetes. Therefore, we focused on the Th1-specific T-box transcription factor gene (T-bet), which contributes to the induction of the hallmark Th1 cytokine, IFN-γ. We first screened for polymorphisms in the T-bet gene and detected two microsatellite repeat polymorphisms located in intron 1 and the 3′- flanking region, and two single nucleotide polymorphisms, including a His33Gln substitution within the coding region. By association studies, the Gln-positive phenotype and (CA)14 allele in 3′-flanking region of T-bet were found to be associated with type 1 diabetes in the Japanese population. Furthermore, Gln33 T-bet showed a significantly higher transcriptional activity of the IFNG gene via a dual luciferase reporter assay. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the T-bet gene, and that variation in T-bet transcriptional activity may play a role in the development of type 1 diabetes, possibly through the effect on IFN-γ production in Th1 cells.

Association between birthweight and body mass index at 3 years of age.

Abstract Background : Obesity in children is one of the risk factors for adulthood obesity, which then leads to the development of chronic diseases such as hypertension, hyperlipidemia and diabetes. In this study, we identified significant factors associating with the body mass index (BMI) at 3 years of age from the perinatal characteristics of children.

Quantification of circulating varicella zoster virus-DNA for the early diagnosis of visceral varicella

Varicella zoster virus (VZV)-DNA was quantified in peripheral blood of 2 patients with visceral varicella due to endogenous reactivation. An 18-year-old male contracted varicella following the courses of chemotherapy for T cell lymphoma. Another 18-year-old male suffered from varicella 16 months after the complete engraftment of hematopoietic stem cell transplantation. Both patients had past VZV infection, but no recent contact with the disease. Paralytic ileus and ascites preceded the skin lesions. Quantitative real-time polymerase chain reaction revealed >200 copies of VZV per 1 ml of whole blood before or at the time when cropping vesicles emerged. The viral load reflected their prolonged clinical courses. Similar levels of VZV-DNA were detected in primary varicella patients, but not in herpes zoster patients or immunocompromised children without varicella or zoster. Quantitative monitoring of circulating VZV-DNA may be useful for the diagnosis and assessing the treatment response of visceral varicella in immunocompromized hosts.

Genomic structure of the human glucose 6-phosphate translocase gene and novel mutations in the gene of a Japanese patient with glycogen storage disease type Ib.

Glycogen storage disease (GSD) type Ib is an autosomal recessive disorder caused by a deficiency in microsomal glucose 6-phosphate (G6P) translocase. A gene mutated in GSD type Ib patients has recently been isolated. We have determined the entire sequence of the human G6P translocase gene by PCR-directed sequencing. The gene spans approximately 5 kb of genomic DNA and contains eight exons. Analysis of DNA from a Japanese patient with GSD type Ib revealed new compound heterozygous mutations; a T to C transition at cDNA position 521 resulting in W118R, and an A to C transversion at the –2 splicing acceptor site of intron 1. Reverse transcription (RT)-PCR from leukocyte RNA of the patient revealed the abnormally spliced transcript. These results further support the suggestion that the gene is causative for GSD Ib and should be useful in the molecular diagnosis of such patients.

Hypothalamic hamartoma associated with an arachnoid cyst

A hypothalamic hamartoma associated with an arachnoid cyst in an 8-year-old boy is reported herein. He presented with precocious puberty, and neuroimaging studies demonstrated a solid mass in the prepontine cistern and a huge arachnoid cyst in the left cranial fossa. The mass appeared isointense to the surrounding cerebral cortex on T1-weighted magnetic resonance images, hyperintense on T2-weighted images, and was not enhanced after administration of Gd-DTPA. The patient underwent a left frontotemporal craniotomy and a cyst-peritoneal shunt was inserted. Histological features of the cyst wall and the mass were characteristic of an arachnoid cyst and hamartoma, respectively. While a hypothalamic hamartoma associated with an arachnoid cyst is rare, such a case may help clarify the geneses of both anomalous lesions.

Body composition, atherogenic risk factors and apolipoproteins following growth hormone treatment

We studied the change in atherogenic risk factors in 27 children, 21 boys and 6 girls, 6 to 14 years of age. with growth hormone deficiency during 12 months of growth hormone replacement therapy. Changes in body composition and lipid profile during growth hormone treatment were evaluated. The atherogenic index was calculated using the equation [(total cholesterol ‐ high‐density lipoprotein cholesterol)(apolipoprotein B)] / [(apolipoprotein A1)(high‐density lipoprotein cholesterol)]. Body fat decreased (p < 0.01), associated with an increase in lean body mass (p < 0.01). Total cholesterol and high‐density lipoprotein cholesterol showed no significant changes. The atherogenic index significantly decreased from 1.44 ± 0.60 to 1.09 ± 0.52 (p < 0.01) after 12 months. Apolipoproteins Cu and Cm increased throughout the study period (p < 0.01). Lipoprotein(a) and apolipoproteins A1, B and B/A1 ratio did not change significantly. In conclusion, growth hormone treatment improved body composition and reduced atherogenic risk factors in children with growth hormone deficiency.

Late-onset ornithine transcarbamylase deficiency in male patients : prognostic factors and characteristics of plasma amino acid profile

Background: The occurrence of male patients with ornithine transcarbamylase (OTC) deficiency during adolescence or in adulthood has now been recognized. The aim of this study was to determine the prognostic factors that affect the prognosis of life, to explore a basis for therapeutic strategy.

Rubinstein-Taybi syndrome: a girl with a history of neuroblastoma and premature thelarche.

A 7-year-old girl with Rubinstein-Taybi syndrome (RTS) who had a history of neuroblastoma and premature thelarche is reported. The neuroblastoma was detected at age 6 months on a nation-wide neuroblastoma screening program, surgically removed, and took a favorable clinical course with minimal therapy. She developed isolated breasts at age 6 years, had normal plasma levels of estradiol, follicular-stimulating hormone (FSH), and luteinizing hormone (LH), and showed a FSH-predominant pattern on the LH-releasing hormone stimulation test. In view of these findings, she was diagnosed to have premature thelarche. Premature thelarche may not be uncommon in girls with RTS.

The Leu544Ile polymorphism of the growth hormone receptor gene affects the serum cholesterol levels during GH treatment in children with GH deficiency.

Objective  The cellular effects of growth hormone (GH) are mediated by the interaction between GH and the GH receptor (GHR). We investigated the association between polymorphisms in GHR and changes in height standard deviation scores (SDS), and lipid metabolism during GH treatment for GH‐deficient children.

Association study between interleukin-12 receptor β1/β2 genes and type 1 diabetes or asthma in the Japanese population

Interleukin-12 (IL-12) secreted from macrophages or dendritic cells plays an important role in the protection against intracellular pathogens as well as the developmental commitment of T helper 1 cells. IL-12 exerts its biological effects through binding to specific IL-12 receptors (IL-12Rs) termed IL-12Rβ1 and IL 12Rβ2. In this paper, we performed association studies between the three reported polymorphisms (Q214R, M365T and G378R) of the IL-12Rβ1 gene or the newly identified polymorphisms (P238L, IVS9 −7G>A, IVS13 –121G>A, A643T, P779P and c.3283T>G) of the IL-12Rβ2 gene, and the development of type 1 diabetes or atopic asthma as representative Th1- and Th2- dominant diseases, respectively. The association study of each polymorphism of the IL-12Rβ1 or IL-12Rβ2 gene and type 1 diabetes or asthma showed that these IL-12R genes did not contribute to the development of type 1 diabetes or asthma in the Japanese population. Further analysis in individuals with susceptibility to intracellular pathogens may elucidate the importance of the IL-12R genes.