-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: To elucidate the pathogenesis of isolated growth hormone (GH) deficiency in a Japanese girl without consanguinity. DESIGN: A 2-year-old girl of height 77.2cm (-3.0 SD for Japanese girls) was found to have an insulin-like growth factor (IGF)-1 level of 7ng/mL and IGF binding protein-3 (IGFBP-3) level of 0.41μg/mL. GH responded modestly to a series of pharmacological stimulants, increasing to 2.81ng/mL with insulin-induced hypoglycemia, 3.78ng/mL with arginine, and 3.93 with GH-releasing hormone (GHRH). Following direct sequencing of the GHRH receptor (GHRHR) gene, evaluation by the luciferase reporter assay, immunofluorescence study, and in vitro splicing assay with minigene constructs was conducted. RESULTS: Novel compound heterozygous GHRHR gene mutations were identified in the patient. A p.G136V substitution elicited no luciferase activity increment in response to GHRH stimulation, with normal membranous expression. Splicing assay demonstrated that the IVS2+3a>g mutation would lead to aberrant splicing. CONCLUSIONS: A case of isolated GH deficiency due to novel GHRHR gene mutations was identified.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 04/2013; · 2.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fat-mass and obesity-associated (FTO) gene is known to be involved in the pathophysiology of obesity and a single-nucleotide polymorphism (SNP) rs9939609 of FTO gene is repeatedly confirmed to be associated with body mass index (BMI) and obesity. The aim of this study is to elucidate effects of FTO gene polymorphism on BMI in Japanese patients with schizophrenia and healthy subjects.
Three hundred fifty one patients with schizophrenia and 342 age- and sex-matched healthy subjects participated in the study. Information on BMI and antipsychotic medication was also collected from patients and healthy subjects. Genotype of the FTO SNP rs9939609 was determined by TaqMan SNP Genotyping Assays.
There was no significant difference in BMI between patients and healthy subjects. No significant difference in BMI was observed among any medications. We observed no significant difference in rs9939609 allele frequencies between patients and healthy subjects. There was a significant difference in BMI between healthy subjects with risk (AA or TA) genotypes and those with TT genotype. We also observed a significant positive correlation between the number of risk allele (A allele) and BMI in healthy subjects.
Our study suggested that FTO rs9939609 polymorphism might have some impacts on the BMI in healthy subjects, but might not have same impacts on the BMI of patients with schizophrenia.
Clinical Psychopharmacology and Neuroscience 12/2012; 10(3):185-9.
-
Biological Psychiatry 08/2012; 141(2-3):271-3. · 8.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously identified significant quantitative trait loci (QTL) Dbm1 (diabetic modifier QTL 1) on chromosome 6, affecting plasma glucose and insulin concentrations and body weight on F(2) progeny of hypoinsulinemic diabetic Akita mice, with the heterozygous Ins2 gene Cys96Tyr mutation, and non-diabetic A/J mice. To discover diabetic modifier genes on Dbm1, we constructed congenic strain for Dbm1 using the Akita allele as donor in A/J allele genetic background, and compared diabetes-related phenotypes to control mice. The homozygote for Akita allele of Dbm1 was associated with lower plasma glucose concentrations in glucose tolerance test (GTT) in the hypoinsulinemic condition derived from the Ins2 mutation and lower plasma insulin concentrations and body weight in the normoinsulinemic condition without the Ins2 mutation than the homozygote for A/J allele, as we performed QTL analysis on F(2) intercross mice. The Akita allele also decreased the epididymal white adipose tissue (EWAT) weight. According to the analysis of sub-congenic strains, we narrowed down the responsible diabetic modifier region to 9 Mb. As fourteen candidate genes exist in this region, we analyzed genomic variants of these genes and gene expression in the muscle, liver, and EWAT and identified that Bhlhe40 gene expression in muscle is decreased in congenic mice. According to the in vitro functional analyses, Bhlhe40 was shown to negatively control fatty acid oxidation in cultured myocyte. Based on these, we conclude that Bhlhe40 is a possible candidate diabetic modifier gene responsible for Dbm1 locus affecting diabetes and/or obesity through negatively controlling fatty acid oxidation in muscle.
Genes & Genetic Systems 01/2012; 87(4):253-64. · 0.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously identified four significant quantitative trait loci (QTL) affecting plasma glucose concentrations on F(2) progeny of hypoinsulinemic diabetic Akita mice, heterozygous for the Ins2 gene Cys96Tyr mutation, and non-diabetic A/J mice, one of which on chromosome 15 named Dbm4 (diabetic modifier QTL 4) was shown to affect fasting plasma glucose concentrations with a maximum LOD score of 6.17. To estimate the influence of Dbm4 itself to the diabetes-related phenotypes, we constructed congenic strain with heterozygous Ins2 mutation using the Akita allele as donor of Dbm4 locus in the A/J genetic background, and measured quantitative traits including plasma glucose concentrations in glucose tolerance test (GTT). In this study, we found the Akita allele in Dbm4 was associated with higher fasting plasma glucose concentrations as in previous QTL analysis. According to gene expression assay, key enzymes of hepatic gluconeogenesis were expressed to the more increased degree in the liver of congenic mice compared to the A/J allele based control mice. Based on these results, we concluded that diabetic modifier gene(s) exist on Dbm4 locus affecting fasting plasma glucose concentrations via regulation of gluconeogenic gene expression in the hypoinsulinemic diabetic condition. Identification of the modifier gene responsible for Dbm4 would provide new drug development targets for human type 2 diabetes with hepatic insulin resistance.
Genes & Genetic Systems 01/2012; 87(5):341-6. · 0.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In the current study, to elucidate the molecular basis of cell type-specific expression of the GH-secretagogue/ghrelin receptor type 1A (GHSR1A), we characterized the structure and putative promoter region of the rat Ghsr gene. We identified an alternative 5'-untranslated first exon that contains multiple transcription start sites, and confirmed a 200-bp sequence proximal to this exon to be sufficient for basal promoter activity. A promoter-associated CpG island conserved across different species was found to be hypomethylated in Ghsr1a-expressing cell lines, while being heavily methylated in non-expressing cells. In cells with low or absent Ghsr1a expression, treatment with demethylating agents activated Ghsr1a transcription. Chromatin immunoprecipitation assays demonstrated Ghsr1a-expressing cells to display active histone modifications, whereas repressive modifications were present exclusively in other cell types. These results suggest epigenetic modifications at GHSR to play important roles in determining GHSR1A expression and abundance, and therefore the consequent sensitivity of cells to ghrelin.
Molecular and Cellular Endocrinology 07/2011; 345(1-2):1-15. · 4.19 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To date, approximately 35 different POU1F1 mutations have been described in patients with familial and sporadic combined pituitary hormone deficiency (CPHD) from different ethnic backgrounds. The majority are missense mutations clustered within the conserved POU-specific and POU-homeo domains, encoded by exons 4 and 6, respectively.
This study aimed to identify the molecular basis and clinical characteristics of a Japanese CPHD family with a novel POU1F1 mutation.
The POU1F1 gene was sequenced in identical twin brothers with mild CPHD. The mutation identified was also evaluated in family members as well as 188 Japanese controls and then examined in functional studies.
A novel heterozygous splice site mutation (Ex2 + 1G>T; c.214 + 1G>T) was detected. This mutation was also present in their undiagnosed mother, but not in any of the controls. In vitro splicing studies suggested this mutation to result in an in-frame skipping of exon 2, thus producing an internally deleted protein lacking most of the R2 transactivation subdomain (TAD-R2). Heterologous expression studies of the mutated POU1F1 protein showed only modest reductions in its transactivation activities in HEK293T cells, while acting as a dominant-negative inhibitor of the endogenous activities of POU1F1 in pituitary GH3 cells.
This is the first report of a mutation at the exon 2 donor splice site of POU1F1, affecting TAD-R2. The addition of this mutation to the growing list of pathological POU1F1 mutations may provide deeper insights into clinical heterogeneity in the expressions of individual mutations and a better understanding of the structure-function relationships of POU1F1.
Clinical Endocrinology 07/2011; 76(1):78-87. · 3.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Short stature (SS) is a multifactorial developmental condition with a significant genetic component. Recent studies have revealed that rare deleterious mutations in the GH-secretagogue receptor type 1A (GHSR1A) gene could be a cause of familial SS or GH deficiency.
The aim of this study was to evaluate the contribution of GHSR1A mutations to the molecular mechanism underlying SS in Japanese subjects.
We performed mutational screening of the GHSR1A gene in 127 unrelated Japanese SS patients diagnosed with either isolated GH deficiency or idiopathic SS. Identified mutations were analyzed in 188 control subjects, and their functional properties were examined in a heterologous expression system.
Four novel heterozygous GHSR1A mutations were identified (ΔQ36, P108L, C173R, and D246A). Expression studies demonstrated that these mutations had varying functional consequences: 1) all mutations showed a loss-of-function effect on the constitutive signaling activity of GHSR1A, but the degree of loss varied widely; 2) C173R caused intracellular retention of the mutated protein, resulting in total loss of receptor function; 3) P108L resulted in a large decrease in binding affinity to ghrelin, without affecting its surface expression; 4) D246A uniquely impaired agonist- and inverse agonist-stimulated receptor signaling; and 5) ΔQ36 showed only a subtle reduction in constitutive activity. The cumulative frequency of these putative functional mutations was significantly higher in the patient group than in controls (4.72 vs. 0.53%; P = 0.019; odds ratio = 9.28; 95% confidence interval, 1.10-78.0).
Our results suggest that GHSR1A mutations contribute to the genetic etiology of SS in the Japanese population.
The Journal of clinical endocrinology and metabolism 11/2010; 96(2):E373-8. · 6.50 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Growth hormone-releasing hormone receptor (GHRHR) gene mutations have been identified in patients of different ethnic origins with isolated GH deficiency (IGHD) type IB. However, the prevalence of these mutations in the Japanese population has yet to be fully determined.
This study aimed to evaluate the contributions of GHRHR mutations to the molecular mechanism underlying short stature in Japanese subjects.
The GHRHR gene was sequenced in 127 unrelated Japanese patients with either IGHD (n = 14) or idiopathic short stature (ISS; n = 113). Sequence variants were evaluated in family members and 188 controls, and then examined in functional studies.
A novel homozygous E382E (c.1146G>A) synonymous variant, at the last base of exon 12, was identified in an IGHD family with two affected sisters. In vitro splicing studies showed this mutation to result in skipping of exon 12. In one ISS patient, a heterozygous ATG-166T>C variant was found in the distal Pit-1 P2 binding element of the GHRHR promoter. In two control subjects, a close but distinct variant, ATG-164T>C, was detected. Functional studies showed that both promoter variants diminish promoter activity by altering Pit-1 binding ability. Four missense variants were also found in both patient and control groups but had no detectable functional consequences.
The homozygous GHRHR mutation was rare, being detected in only one Japanese IGHD family. Future research is needed to clarify the genetic contributions of heterozygous functional promoter variants to GHD, ISS and normal-stature variations.
Clinical Endocrinology 11/2010; 74(2):223-33. · 3.17 Impact Factor
-
Véronique Bolduc,
Gareth Marlow,
Kym M Boycott,
Khalil Saleki,
Hiroshi Inoue,
Johan Kroon, Mitsuo Itakura,
Yves Robitaille,
Lucie Parent,
Frank Baas,
Kuniko Mizuta,
Nobuyuki Kamata,
Isabelle Richard,
Wim H J P Linssen,
Ibrahim Mahjneh,
Marianne de Visser,
Rumaisa Bashir,
Bernard Brais
[show abstract]
[hide abstract]
ABSTRACT: The recently described human anion channel Anoctamin (ANO) protein family comprises at least ten members, many of which have been shown to correspond to calcium-activated chloride channels. To date, the only reported human mutations in this family of genes are dominant mutations in ANO5 (TMEM16E, GDD1) in the rare skeletal disorder gnathodiaphyseal dysplasia. We have identified recessive mutations in ANO5 that result in a proximal limb-girdle muscular dystrophy (LGMD2L) in three French Canadian families and in a distal non-dysferlin Miyoshi myopathy (MMD3) in Dutch and Finnish families. These mutations consist of a splice site, one base pair duplication shared by French Canadian and Dutch cases, and two missense mutations. The splice site and the duplication mutations introduce premature-termination codons and consequently trigger nonsense-mediated mRNA decay, suggesting an underlining loss-of-function mechanism. The LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii atrophy. The MMD3 phenotype is associated with distal weakness, of calf muscles in particular. With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The phenotypic heterogeneity associated with ANO5 mutations is reminiscent of that observed with Dysferlin (DYSF) mutations that can cause both LGMD2B and Miyoshi myopathy (MMD1). In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies. Though the function of the ANO5 protein is still unknown, its putative calcium-activated chloride channel function may lead to important insights into the role of deficient skeletal muscle membrane repair in muscular dystrophies.
The American Journal of Human Genetics 02/2010; 86(2):213-21. · 10.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We report on a Japanese girl with HDR (hypoparathyroidism, sensorineural deafness, and renal dysplasia) syndrome who developed diabetes mellitus (DM) at three years of age (blood glucose 713 mg/dL, HbA(1c) 8.0%) in the absence of anti-glutamic acid decarboxylase autoantibodies. Mutation analysis revealed a de novo heterozygous two base pair deletion at exon 6 of the GATA3 gene (c.1200_1201delCA; p.H400fsX506). GATA3 expression was identified by PCR amplification for human pancreas cDNA, and mouse Gata3 was weekly but unequivocally expressed in pancreatic beta cells. The results, in conjunction with the previous findings indicating the critical role of GATA3 in lymphocyte function, GATA3 haploinsufficiency may affect the function of beta cells and/or lymphocytes, leading to the development of DM in relatively exceptional patients with high susceptibility to DM.
Endocrine Journal 12/2009; 57(2):171-4. · 2.03 Impact Factor
-
Shusuke Numata,
Masahito Nakataki,
Jun-ichi Iga,
Toshihito Tanahashi,
Yoshihiro Nakadoi,
Kazutaka Ohi,
Ryota Hashimoto,
Masatoshi Takeda, Mitsuo Itakura,
Shu-ichi Ueno,
Tetsuro Ohmori
[show abstract]
[hide abstract]
ABSTRACT: Disrupted-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia (SZ) and major depressive disorder (MDD), interacts with several proteins and some of them are reported to be genetically associated with SZ. Pericentrin (PCNT) also interacts with DISC1 and recently single-nucleotide polymorphisms (SNPs) within the PCNT gene have been found to show significant associations with SZ and MDD. In this study, case-controlled association analysis was performed to determine if the PCNT gene is implicated in SZ. Nine SNPs were analyzed in 1,477 individuals (726 patients with SZ and 751 healthy controls). No significant difference was observed between the controls and the patients in allelic frequencies or genotypic distributions of eight SNPs. Although allelic distribution of rs11702684 was different between the two groups (P = 0.042), the difference did not reach statistical significance after permutation correction for multiple comparisons. In the haplotypic analysis, we could not find any significant association in our subjects, either. This gene may not play a major role independently in the etiology of SZ in the Japanese population.
Neuromolecular medicine 11/2009; 12(3):243-7. · 5.00 Impact Factor
-
Psychiatric genetics 07/2009; 19(3):162. · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Pericentrin (PCNT) interacts with disruption-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). We sought to determine whether the PCNT gene is implicated in MDD.
We performed case-control association analyses in the Japanese population. We analyzed 9 single nucleotide polymorphisms (SNPs) in 173 patients with MDD and 348 healthy controls.
We found a significant allelic association between 3 SNPs (rs3788265, rs2073376 and rs2073380) of the PCNT gene and MDD (p = 0.006, 0.005 and 0.021, respectively). After correction for multiple testing, 2 SNPs (rs3788265 and rs2073376) retained significant allelic associations with MDD. In addition, we found a significant association between the 2 marker haplotypes (r3788265 and rs2073376) and MDD (permutation p = 0.011).
Our sample was small and comprised only Japanese participants. In addition, owing to the late onset of MDD, it is possible that the disorder will develop in at least some participants in our control group. Finally, we did not show how SNPs of the PCNT gene alter its function.
Our results suggest that genetic variations in the PCNT gene may play a significant role in the etiology of MDD in the Japanese population.
Journal of psychiatry & neuroscience: JPN 06/2009; 34(3):195-8. · 5.34 Impact Factor
-
K Nishimoto,
Y Kochi,
K Ikari,
K Yamamoto,
A Suzuki,
K Shimane,
Y Nakamura,
K Yano,
N Iikuni,
S Tsukahara, [......],
Y Toyama,
T Horiuchi,
K Tao,
K Yasutomo,
D Hamada,
N Yasui,
H Inoue, M Itakura,
H Yamanaka,
S Momohara
[show abstract]
[hide abstract]
ABSTRACT: The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analysed.
A multicentre association study consisting of 4 RA case-control series (4397 cases and 2857 controls) and 3 SLE case-control series (591 cases and 2199 shared controls) was conducted. Genotyping was performed using TaqMan genotyping assay for two single nucleotide polymorphisms (SNPs) that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay.
Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between patients with SLE and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in the present study, while they decreased the risk in the original studies. A significant difference was found between risk allele carriers and non-carriers of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymphoblastoid cell lines (p = 0.04).
Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.
Annals of the rheumatic diseases 04/2009; 69(2):368-73. · 8.11 Impact Factor
-
Zhi Rong Qian,
Sylvia L Asa,
Haruhiko Siomi,
Mikiko C Siomi,
Katsuhiko Yoshimoto,
Shozo Yamada,
Elaine Lu Wang,
Md Mustafizur Rahman,
Hiroshi Inoue, Mitsuo Itakura,
Eiji Kudo,
Toshiaki Sano
[show abstract]
[hide abstract]
ABSTRACT: High-mobility group A2 is highly expressed during embryogenesis and in various benign and malignant tumors. Recent studies report that high-mobility group A2 is negatively regulated by the let-7 microRNAs (miRNAs) family in vitro. The development of pituitary adenomas in high-mobility group A2 transgenic mice showed that high-mobility group A2 may be involved in pituitary tumorigenesis. However, no studies have investigated the clinical significance of high-mobility group A2 and its relationship to the let-7 miRNA family in human pituitary adenomas. Using immunohistochemistry, we analyzed high-mobility group A2 expression with respect to various clinicopathologic factors in 98 pituitary adenomas. Overexpression of high-mobility group A2 was observed in 39% (38/98) of pituitary adenomas compared with normal adenohypophysial tissue and was frequently found in adenomas including prolactin (PRL), adrenocorticotrophic hormone, or follicle-stimulating hormone/luteinizing hormone and in null cell adenomas, but relatively rare in growth hormone (GH) and mixed GH/PRL adenomas. High-mobility group A2 expression was significantly associated with tumor invasion (P<0.05) and was significantly higher in grade IV than in grades I, II, and III adenomas (P<0.05). High levels of high-mobility group A2 expression were more frequently observed in macroadenomas than in microadenomas (P<0.05). High levels of high-mobility group A2 expression also significantly correlated with the proliferation marker Ki-67 (P<0.0001). Real-time quantitative RT-PCR analysis was carried out to evaluate the expression of let-7 in 55 pituitary adenomas. Subsequently, decreased expression of let-7 was confirmed in 23 of 55 (42%) adenomas and was correlated with high-grade tumors (P<0.05). An inverse correlation between let-7 and high-mobility group A2 expression was evident (R=−0.33, P<0.05). These findings support a causal link between let-7 and high-mobility group A2 whereby loss of let-7 expression induces high-mobility group A2 upregulation that represents an important mechanism in pituitary tumorigenesis and progression.Keywords: pituitary adenoma, HMGA2, let-7, tumorigenesis
Modern Pathology 01/2009; 22(3):431-441. · 4.79 Impact Factor
-
Kiyoshi Kunika,
Toshihito Tanahashi,
Shusuke Numata,
Shu-ichi Ueno,
Tetsuro Ohmori,
Naoto Nakamura,
Kazue Tsugawa,
Katsuyuki Miyawaki,
Maki Moritani,
Hiroshi Inoue, Mitsuo Itakura
[show abstract]
[hide abstract]
ABSTRACT: Genetic variants of the transcription factor 7-like 2 (TCF7L2) gene affect the risk of type 2 diabetes in populations with multiple ethnic groups. However, a comprehensive survey of this gene has not been done for a Japanese population. Thus, we conducted this gene-based association study, in which the common genetic variants were analyzed. Using 24 Japanese type 2 diabetic subjects, we first screened a 9.5 kb region, which included the entire coding sequence, to assess potential functional variants of TCF7L2. Sequencing revealed a common coding variant (Pro477Thr) in exon 14 of TCF7L2 that was not enrolled in the public SNP database. Nineteen SNPs and the microsatellite DG10S478 were genotyped across the gene in 2,877 unrelated Japanese subjects. This independent screen identified the previously reported rs7903146 with a strongest association (allele P = 0.0001, odds ratio = 1.59 [95% confidence interval 1.25-2.01]), but there was no significant association between Pro477Thr and type 2 diabetes (allele P = 0.64). Expression of the Pro477Thr variant did not alter TCF7L2 expression in 30 lymphoblast cells. Although a genotypic effect of Pro477Thr on expression of TCF7L2 was not apparent, Pro477Thr was identified as a common variant of TCF7L2 in 2,877 Japanese subjects. Further functional studies are required to determine the possible effect of this coding variant on type 2 diabetes.
Journal of Human Genetics 12/2008; 53(11-12):972-82. · 2.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: D4-GDI, a Rho guanosine diphosphate (GDP) dissociation inhibitor, is preferentially expressed in hematopoietic tissues and binds to a small GTP-binding protein, Rho, and inhibits GDP dissociation from Rho. We identified point mutations in the D4-GDI gene in human leukemic cells. We therefore investigated the functions of D4-GDI and mutated D4-GDI in T cells. Transgenic mice (Tg) harboring human wild-type and mutant D4-GDI transgenes driven by the lck promoter were generated. Cellular immunity responses against cytozoic pathogens were examined. The cytoskeletal organization in the CD3+T cells and the proliferation of splenocytes by Con A were investigated in both Tg and littermates (LMs). Granuloma formation by bacille Calmette-Guerin was impaired in the wild-type D4-GDI Tg. On the other hand, the number of granulomas of the mutated D4-Tg was significantly higher. Infection with Listeria was more rapidly fatal to wild-type D4-GDI Tg than to LMs, while the survival of mutated D4-GDI Tg was prolonged. The CD3+T cells in wild-type D4-GDI Tg showed an impairment in the formation of stress fibers on anti-CD3 antibody-coated plates, whereas the cytoskeletal organization in CD3+T cells of the mutated D4-GDI Tg was augmented. The proliferation of splenocytes after Con A stimulation was higher in the mutated D4-GDI Tg than in the LMs. D4-GDI may have important functions, such as induction of T cell migration, adhesion and/or proliferation in inflammatory foci, in cellular immunity responses to cytozoic pathogens.
International Immunology 09/2008; 20(10):1299-311. · 3.41 Impact Factor
-
Shusuke Numata,
Jun-Ichi Iga,
Masahito Nakataki,
Shin'ya Tayoshi,
Kyoko Taniguchi,
Satsuki Sumitani,
Masahito Tomotake,
Toshihito Tanahashi, Mitsuo Itakura,
Yoko Kamegaya,
Masahiko Tatsumi,
Akira Sano,
Takashi Asada,
Hiroshi Kunugi,
Shu-Ichi Ueno,
Tetsuro Ohmori
[show abstract]
[hide abstract]
ABSTRACT: The phosphodiesterase 4B (PDE4B) interacts with disrupted-in-schizophrenia 1 (DISC1), which is a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). PDE4B is also important in the regulation of cAMP signaling, a second messenger implicated in learning, memory, and mood. In this study, we determined mRNA expression levels of the PDE4B gene in the peripheral blood leukocytes of patients with MDD and control subjects (n = 33, each). Next we performed two-stage case-controlled association analyses (first set; case = 174, controls = 348; second set; case = 481, controls = 812) in the Japanese population to determine if the PDE4B gene is implicated in MDD. In the leukocytes, a significantly higher expression of the PDE4B mRNA was observed in the drug-naïve MDD patients compared with control subjects (P < 0.0001) and the expression of the MDD patients significantly decreased after antidepressant treatment (P = 0.030). In the association analysis, we observed significant allelic associations of four SNPs (the most significant, rs472952; P = 0.002) and a significant haplotypic association (permutation P = 0.019) between the PDE4B gene and MDD in the first-set samples. However, we could not confirm these significant associations in the following independent second-set of samples. Our results suggest that the PDE4B gene itself does not link to MDD but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 09/2008; 150B(4):527-34. · 3.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In an attempt to rectify the hyperglycemic state in obese insulin resistant db/db mice, a transgenic line was generated (db/db-CDK4(R24C)) that expresses a constitutively active form of cyclin-dependent kinase 4 (CDK4/R24C) under the control of the insulin promoter. Compared with non-transgenic db/db littermates, adult db/db-CDK4(R24C) mice show near-complete glycemic normalization and improved plasma lipid concentrations, but are also more susceptible to weight gain and have significantly lower plasma adiponection levels. They have striking islet hypertrophy and beta-cell hyperplasia, and retain an insulin secretory response during the glucose tolerance test. We examined the expression of several key regulatory transcription factor genes involved in lipid and glucose metabolism in insulin target tissues of db/db-CDK4(R24C) as well as db/db mice, and found that the expression levels of members of the peroxisome proliferator-activated receptor (PPAR) family are highly associated with metabolic alterations in a gene- and tissue-specific manner. We show for the first time that the Ppar-delta in skeletal muscle and white adipose tissues is transcriptionally down-regulated in db/db mice. The db/db-CDK4(R24C) mice present a novel model of leptin-resistant obesity with compensatory hyperinsulinemia and normalized blood glucose levels, and thus may be useful for future studies that aim to dissect relationships between insulin and leptin signaling.
Diabetes research and clinical practice 09/2008; 82(1):33-41. · 2.16 Impact Factor
