Tadayuki Ayabe

Human glutathione S-transferase A (GSTA) family genes are regulated by steroidogenic factor 1 (SF-1) and are involved in steroidogenesis

Steroidogenic factor 1 (SF‐1) is a master regulator for steroidogenesis. In this study, we identified novel SF‐1 target genes using a genome‐wide promoter tiling array and a DNA microarray. SF‐1 was found to regulate human glutathione S‐transferase A (GSTA) family genes (hGSTA1–hGSTA4), a superfamily of detoxification enzymes clustered on chromosome 6p12. All hGSTA genes were up‐regulated by transduction of SF‐1 into human mesenchymal stem cells, while knockdown of endogenous SF‐1 in H295R cells down‐regulated all hGSTA genes. Chromatin immunoprecipitation assays, however, revealed that SF‐1 bound directly to the promoters of hGSTA3 and weakly of hGSTA4. Chromosome conformation capture assays revealed that the coordinated expression of the genes was based on changes in higher‐order chromatin structure triggered by SF‐1, which enables the formation of long‐range interactions, at least between hGSTA1 and hGSTA3 gene promoters. In steroidogenesis, dehydrogenation of the 3‐hydroxy group and subsequent Δ5‐Δ4 isomerization are thought to be enzymatic properties of 3β‐hydroxysteroid dehydrogenase (3β‐HSD). Here, we demonstrated that, in steroidogenic cells, the hGSTA1 and hGSTA3 gene products catalyze Δ5‐Δ4 isomerization in a coordinated fashion with 3β‐HSD II to produce progesterone or Δ4‐androstenedione from their Δ5‐precursors. Thus, hGSTA1 and hGSTA3 gene products are new members of steroidogenesis working as Δ5‐Δ4 isomerases.—Matsumura, T., Imamichi, Y., Mizutani, T., Ju, Y., Yazawa, T., Kawabe, S., Kanno, M., Ayabe, T., Katsumata, N., Fukami, M., Inatani, M., Akagi, Y., Umezawa, A., Ogata, T., Miyamoto, K., Human glutathione S‐transferase A (GSTA) family genes are regulated by steroidogenic factor 1 (SF‐1) and are involved in steroidogenesis. FASEB J. 27, 3198–3208 (2013). www.fasebj.org

Decline of CSF orexin (hypocretin) levels in Prader–Willi syndrome

Prader–Willi syndrome is a congenital neurodevelopmental disorder resulting from deletion of the paternal copies of genes within the chromosome region 15q11‐q13. Patients with Prader–Willi syndrome often exhibit excessive daytime sleepiness, excessive appetite, and obesity. As is the case in narcolepsy, orexin (hypocretin) may be responsible for these symptoms. However, reports showing cerebrospinal fluid orexin levels in Prader–Willi syndrome patients have been limited. The aim of this study was to examine the relationship between the characteristic symptoms of Prader–Willi syndrome and cerebrospinal fluid orexin levels. We clinically identified 14 Prader–Willi syndrome patients and examined their cerebrospinal fluid orexin levels. A total of 12 patients with a 15q11‐q13 deletion and two patients with maternal uniparental disomy of chromosome 15 were identified. A total of 37 narcoleptic patients and 14 idiopathic hypersomnia patients were recruited for comparison. Cerebrospinal fluid orexin levels (median [25–75 percentiles]) in the 14 Prader–Willi syndrome patients were intermediate (192 [161–234.5] pg/ml), higher than in the narcoleptic patients, but lower than in the idiopathic hypersomnia patients. Body mass index of the Prader–Willi syndrome patients was higher than in the narcoleptic and idiopathic hypersomnia patients. There was also a negative correlation between Epworth sleepiness scale scores and orexin levels in Prader–Willi syndrome patients. Decreased cerebrospinal fluid orexin levels in Prader–Willi syndrome may play an important role in severity of obesity and excessive daytime sleepiness.

46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism.

Stoppa‐Vaucher S, Ayabe T, Paquette J, Patey N, Francoeur D, Vuissoz J‐M, Deladoëy J, Samuels ME, Ogata T, Deal CL. 46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism.

Pyruvate Improved Insulin Secretion Status in a Mitochondrial Diabetes Mellitus Patient

CONTEXT Mitochondrial diabetes is a rare form of diabetes mellitus accounting for up to 1% of all diabetes. Pyruvate therapy has been reported to be a potential therapeutic choice for patients with mitochondrial diseases. CASE DESCRIPTION Water-based sodium pyruvate solutions (0.5 g/kg, thrice daily) were administrated orally to a 32-year-old Japanese male with mitochondrial diabetes and myopathy caused by m.14709T>C mutation. At the age of 20 years, he was diagnosed with diabetes mellitus and started insulin therapy. He tested negative for islet cell and glutamic decarboxylase antibodies. To evaluate favorable therapeutic improvements, we measured the lactate and pyruvate levels in plasma and cerebrospinal fluid; urinary C-peptide, glycated hemoglobin, and glycoalbumin levels; and total daily insulin dose (TDD). The patient experienced no side effects such as diarrhea because of pyruvate therapy. His urinary C-peptide level improved from 4.3 to 17.2 μg/d after 1 day and to 30.2 μg/d after 6 months of pyruvate therapy. TDD decreased from 33 to 20 U/d after 6 months of pyruvate therapy, but the lactate levels of plasma and cerebrospinal fluid and the lactate/pyruvate ratio did not change. CONCLUSIONS Sodium pyruvate improved insulin secretion and resulted in decreased TDD in a patient with mitochondrial diabetes. Pyruvate therapy may be a potential therapeutic choice for patients with mitochondrial diabetes. Clinical trials involving a larger number of patients and long-term evaluation of the therapy are necessary to clarify the efficacy of pyruvate therapy.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age‐specific effects of cis‐regulatory haplotypes at 17q12‐q21

The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non‐white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12‐q21 encompassing rs2290400 are known to determine the susceptibility of early‐onset asthma by affecting the expression of flanking genes.

Characterization of diabetes mellitus in Japanese prader-willi syndrome.

Prader-Willi syndrome (PWS) is frequently associated with marked obesity and diabetes mellitus (DM). Although the overall frequency of DM in PWS ranges from 7–20%, there is only limited data available on Japanese patients. This study evaluated five factors associated with DM in PWS: 1) frequency, 2) age of onset, 3) risk factors, 4) long-term complications and 5) treatment. Sixty-five patients, ranging in age from 10 to 53 yr, were studied retrospectively. The frequency of DM in patients over 10 yr of age was 26.2% (17/65 patients). The age of DM onset ranged from 10 to 29 yr with a median age of 15 yr. The body mass index (BMI) was significantly higher in the DM group in comparison with the non-DM group. The number of patients using growth hormone (GH) in the DM group was significantly lower than the number that did not. Proteinuria (urinary excretion of albumin/creatinine at spot collection: U-Alb/Cr ≥300 mg/gCr) was observed in 1/17 patients (5.9%), microalbuminuria (U-Alb/Cr 30–300 mg/gCr) was observed in 4/17 patients (23.5%) and nonproliferative retinopathy was observed in 2/17 patients (11.8%). Among oral hypoglycemic agents, alpha-glucosidase inhibitors (α-GI) were most often used in our patients (10/17, 58.8%). Eleven out of 17 patients (64.7%) had been treated with insulin.

FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children

To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children.

Gender Differences in the Behavioral Symptom Severity of Prader-Willi Syndrome

Objectives. This study measured gender differences in Prader-Willi syndrome (PWS) in regard to the severity of behavioral symptoms. Methods. The Food Related Problem Questionnaire (FRPQ), the Aberrant Behavior Checklist Japanese Version, the Childhood Routines Inventory, the Pervasive Developmental Disorders Autism Society Japan Rating Scale, and Japanese ADHD-RS were administered to PWS patients (45 males aged 6 to 58 and 37 females aged 6 to 45). To examine the effects that gender and genotype have on the severity of each symptom, two-way ANOVAs were conducted. Results. Significant interactions were found only in regard to FRPQ scores, such as FRPQ total score (F(1, 78) = 8.43, p < 0.01). The FRPQ of male deletion (DEL) individuals was higher than that of female DEL and male mUPD. The FRPQ of male maternal uniparental disomy (mUPD) was lower than that of female mUPD. Conclusions. In terms of problem behaviors, routines, autistic behaviors, and hyperactivity, no significant differences were found. Food-related behaviors in DEL were more severe in males, although those in mUPD were less severe in males.

Chromosome 6q24 methylation defects are uncommon in childhood-onset non-autoimmune diabetes mellitus patients born appropriate- or large-for-gestational age.

Methylation defects in the imprinting locus at chromosome 6q24 result in transient neonatal diabetes and small-for-gestational age (SGA) births (1). These phenotypes are primarily ascribed to the overexpression of PLAGL1, a paternally expressed gene on 6q24 that regulates cell cycle and apoptosis (2). Paternal uniparental disomy involving 6q24, as well as copy-number gains of paternal PLAGL1 alleles and epimutations in maternal alleles, have been identified as the causes of hypomethylation at the differentially methylated region (DMR) of PLAGL1 (3, 4). Recently, Yorifuji et al. reported the identification of 6q24 uniparental disomy in three patients with childhood-onset non-autoimmune diabetes mellitus (5). The three patients were identified through methylation-specific PCR analysis of the PLAGL1 DMR of 113 patients clinically suspected of having maturity-onset diabetes of the young (MODY). These results expanded the phenotypic consequences of 6q24 methylation defects to include MODY-like manifestations without a history of neonatal diabetes. However, the frequency of 6q24 methylation defects among patients with childhood-onset non-autoimmune diabetes remained unknown.

Birth seasonality in Prader-Willi syndrome resulting from chromosome 15 microdeletion†

Birth Seasonality in Prader-Willi Syndrome Resulting From Chromosome 15 Microdeletion Tadayuki Ayabe, Keiko Matsubara, Tsutomu Ogata, Atsuko Ayabe, Nobuyuki Murakami, Toshiro Nagai, and Maki Fukami* Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan Foundation for Growth Science, Tokyo, Japan Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan