Nuclear Factor-1α Gene Research Articles

Land-Use Type Drives Soil Population Structures of the Entomopathogenic Fungal Genus Metarhizium.

Species of the fungal genus Metarhizium are globally distributed pathogens of arthropods, and a number of biological control products based on these fungi have been commercialized to control a variety of pest arthropods. In this study, we investigate the abundance and population structure of Metarhizium spp. in three land-use types—arable land, grassland, and forest—to provide detailed information on habitat selection and the factors that drive the occurrence and abundance of Metarhizium spp. in soil. At 10 sites of each land-use type, which are all part of the Swiss national soil-monitoring network (NABO), Metarhizium spp. were present at 8, 10, and 4 sites, respectively. On average, Metarhizium spp. were most abundant in grassland, followed by forest and then arable land; 349 Metarhizium isolates were collected from the 30 sites, and sequence analyses of the nuclear translation elongation factor 1α gene, as well as microsatellite-based genotyping, revealed the presence of 13 Metarhizium brunneum, 6 Metarhizium robertsii, and 3 Metarhizium guizhouense multilocus genotypes (MLGs). With 259 isolates, M. brunneum was the most abundant species, and significant differences were detected in population structures between forested and unforested sites. Among 15 environmental factors assessed, C:N ratio, basal respiration, total carbon, organic carbon, and bulk density significantly explained the variation among the M. brunneum populations. The information gained in this study will support the selection of best-adapted isolates as biological control agents and will provide additional criteria for the adaptation or development of new pest control strategies.

Early oleate deficiency leads to severe defects in fetal rat liver development.

Objective(s):Oleate can be produced through de novo synthesis, which contributes to biological processes and signaling pathways. However, the role of this non-essential fatty acid in hepatic development remains unclear. The current study aimed to evaluate the influence of early oleate deficiency induced by the inhibitor of de novo oleate synthesis MF-438 on fetal rat liver development.Materials and Methods:Female Wistar rats with an average weight of 200±20 g were subjected to this study. After mating, pregnant rats were divided into three groups and gavaged with the vehicle, MF 438 or MF-438 plus oleate from day 3 of pregnancy for five days. Obtained fetuses were sacrificed and the liver tissues were retrieved. Hepatic morphological index, biochemical markers, and gene expression of hepatic development markers were analyzed using Hematoxylin-Eosine, spectrometry, and real-time PCR techniques, respectively.Results:Relatively, deficient morphological indices and hepatic maturation markers were observed in fetus livers of the inhibitor-treated group. In comparison to the other two groups, total hepatic protein and glycogen content were increased with treatment of MF-438 plus oleate. Hepatocyte nuclear factor 1α, alpha fetoprotein, albumin, and cytochrome P450 gene expression were also significantly increased in the group treated with both MF-438 and oleate.Conclusion:Our data indicate that oleate availability during early embryo development is linked with fetal rat liver development.

Genetic differentiation of Liparus glabrirostris (Curculionidae: Molytinae) populations from the fragmented habitats of the Alps and Carpathian Mountains.

Populations of Liparus glabrirostris (Curculionidae: Molytinae), a weevil inhabiting higher altitudes of Central Europe, were sampled from 24 localities in the Alps and Carpathian Mountains, and the geographical structuring of genetic variation was analyzed. Comparison of the concatenated mitochondrial cytochrome oxidase subunit I and subunit II sequences revealed consistent genetic divergence between the populations of L. glabrirostris from different mountain ranges. In phylogenetic analysis using maximum parsimony and median-joining networks, concatenated mitochondrial haplotypes from the Alps and Carpathians clustered as separate lineages, with high bootstrap support. Substantial genetic distances determined between the separated groups ranged from 2.6 to 3.0%, with divergence estimated to have initiated approximately 0.85-0.98 million years ago. The nuclear elongation factor 1α gene was additionally amplified and haplotype analysis showed very low evolutionary divergence (0.2%), with separate clustering as well. The observed divergence suggests that the populations have been isolated for a long time, as a consequence of environmental changes resulting in varying fragmentation of habitats in the Alps and Carpathians, interrupting genetic exchange events and altering the genetic structure of L. glabrirostris populations. On the other hand, comparison of morphological characteristics showed no differences to confirm genetically well differentiated groups of populations. A polymerase chain reaction and restriction fragment length polymorphism-based method was therefore developed to discriminate between the Alpine and Carpathian lineages.

Studies of genetic variability of the hepatocyte nuclear factor-1α gene in an Indian maturity-onset diabetes of the young family.

Maturity-onset diabetes of the young (MODY), one of the specific types of diabetes mellitus, is a monogenetic disorder characterized by an autosomal dominant (AD) inheritance and β-cell dysfunction. To study an Indian family with clinical diagnosis of MODY and detect the genetic mutations in the aspect of molecular mechanism, seven blood samples were obtained from the diabetic patients of this pedigree and genomic DNA was extracted from peripheral leukocytes. The exon1, exon2 and exon4 of hepatocyte nuclear factor-1α (HNF-1α) gene were amplified by polymerase chain reaction. Then the products were sequenced and compared with standard sequences on gene bank. As a result, two mutations were detected in exon1. That was CTC → CTG (Leu → Leu) in codon17 and ATC → CTC (Ile → Leu) in codon27. I27L was speculated to have a close relationship with the glycometabolism and the pathogenesis of diabetes mellitus together with the putative novel mutation existed in this Indian pedigree. Meanwhile, one mutation of GGG → GGC (Gly → Gly) in codon288 of exon4 was detected in the proband. No mutations were found in exon2 but a G → T base substitution in the intron4 region among all seven samples was detected. It may have some potential effects on the onset of diabetes in this family, but we do not have any evidence right now. Although it requires further investigation on the function of mutations found in the intron region, our research may provide some clue for this issue and it deserves more attention.

BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1α-MODY diabetes.

Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene can lead to diminished amounts of functional HNF-1α, resulting in the onset of a particularly severe form of maturity-onset diabetes of the young (MODY). We have previously shown that induction of a dominant-negative mutant of HNF-1α (DNHNF-1α) results in the activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), preceding the onset of apoptosis and the induction of pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor) as a mediator of DNHNF-1α-induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1α suppression of HNF-1α function in pancreatic beta-cells, this study aimed to examine the effect of loss-of-function of this BH3-only protein on the disease pathology and progression, and further elucidate the role of Bmf in mediating DNHNF-1α-induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in bmf-deficient diabetic male mice and preserved insulin content. Surprisingly, bmf deficiency was found to exacerbate hyperglycemia in both diabetic male and hyperglycemic female mice, and ultimately resulted in a decreased glucose-stimulated insulin response, implicating a role for Bmf in glucose homeostasis regulation independent of an effect on beta-cell loss. Collectively, our data demonstrate that Bmf contributes to the decline in beta-cells in a mouse model of HNF1A-MODY but is also required for the maintenance of glucose homeostasis in vivo.

A novel nonsense mutation of the HNF1α in maturity-onset diabetes of the young type 3 in Asian population

We reported a novel nonsense mutation, R54X of the hepatic nuclear factor 1α (HNF1α) gene in a Chinese family. The mutation was identified in a 47 years old woman and her 19 years old daughter within a five-family members tested. Both the two patients were sensitive to insulin and glibenclamide treatments.

Japanese boy with maturity-onset diabetes of the young type 3 who developed diabetes at 19 months old

Maturity-onset diabetes of the young type 3 (MODY3) is caused by hepatocyte nuclear factor 1α gene mutation and is clinically characterized by young onset and insufficient insulin secretion. We report a 19-month-old Japanese boy with a family history of young-onset diabetes who was initially diagnosed with type 1 diabetes. Mutational analysis of the hepatocyte nuclear factor 1α gene revealed a novel heterozygous frameshift mutation (c.593delA p.Lys198fs) resulting in a truncated protein in the patient and his father. The patient was diagnosed as having MODY3 and was successfully treated with insulin glargine. We could not determine the genetic or environmental factors to explain the difference in the age of disease onset within the same family. This is the youngest case of a MODY3 child presenting with overt diabetes. Our experience suggests that clinicians should always consider the possible diagnosis of MODY3 in a diabetic child with a family history of young-onset diabetes and should perform molecular investigations.

Production of Diabetic Offspring Using Cryopreserved Epididymal Sperm by <i>In Vitro</i> Fertilization and Intrafallopian Insemination Techniques in Transgenic Pigs

Somatic cell nuclear transfer (SCNT) is a useful technique for creating pig strains that model human diseases. However, production of numerous cloned disease model pigs by SCNT for large-scale experiments is impractical due to its complexity and inefficiency. In the present study, we aimed to establish an efficient procedure for proliferating the diabetes model pig carrying the mutant human hepatocyte nuclear factor-1α gene. A founder diabetes transgenic cloned pig was generated by SCNT and treated with insulin to allow for normal growth to maturity, at which point epididymal sperm could be collected for cryopreservation. In vitro fertilization and intrafallopian insemination using the cryopreserved epididymal sperm resulted in diabetes model transgenic offspring. These results suggest that artificial reproductive technology using cryopreserved epididymal sperm could be a practical option for proliferation of genetically modified disease model pigs.

Variants of the HNF1α gene: A molecular approach concerning diabetic patients from southern Brazil.

Maturity Onset Diabetes of the Young (MODY) presents monogenic inheritance and mutation factors which have already been identified in six different genes. Given the wide molecular variation present in the hepatocyte nuclear factor-1α gene (HNF1α) MODY3, the aim of this study was to amplify and sequence the coding regions of this gene in seven patients from the Campos Gerais region, Paraná State, Brazil, presenting clinical MODY3 features. Besides the synonymous variations, A15A, L17L, Q141Q, G288G and T515T, two missense mutations, I27L and A98V, were also detected. Clinical and laboratory data obtained from patients were compared with the molecular findings, including the I27L polymorphism that was revealed in some overweight/obese diabetic patients of this study, this corroborating with the literature. We found certain DNA variations that could explain the hyperglycemic phenotype of the patients.

Species Differentiation of Chinese Mollitrichosiphum (Aphididae: Greenideinae) Driven by Geographical Isolation and Host Plant Acquirement

The impact of both the uplift of the Qinghai-Tibetan Plateau (QTP) and the separation of the Taiwan and Hainan Islands on the evolution of the fauna and flora in adjacent regions has been a topic of considerable interest. Mollitrichosiphum is a polyphagous insect group with a wide range of host plants (14 families) and distributions restricted to Southeast Asia. Based on the mitochondrial Cytochrome C Oxidase Subunit I (COI) and Cytochrome b (Cytb) genes, the nuclear elongation factor-1α (EF-1α) gene, and the detailed distribution and host plant data, we investigated the species differentiation modes of the Chinese Mollitrichosiphum species. Phylogenetic analyses supported the monophyly of Mollitrichosiphum. The divergence time of Mollitrichosiphum tenuicorpus (c. 11.0 mya (million years ago)), Mollitrichosiphum nandii and Mollitrichosiphum montanum (c. 10.6 mya) was within the time frame of the uplift of the QTP. Additionally, basal species mainly fed on Fagaceae, while species that fed on multiple plants diverged considerably later. Ancestral state reconstruction suggests that Fagaceae may be the first acquired host, and the acquisition of new hosts and the expansion of host range may have promoted species differentiation within this genus. Overall, it can be concluded that geographical isolation and the expansion of the host plant range may be the main factors driving species differentiation of Mollitrichosiphum.

Maturity-Onset Diabetes of the Young (MODY) caused by a Novel Nonsense Mutation E41X in the HNF-1α Gene

The most common cause of Maturity-Onset Diabetes of the Young (MODY) are mutations in the Hepatic Nuclear Factor 1α (HNF-1α) gene, resulting in MODY3. In a family afflicted with diabetes, a novel nonsense mutation in HNF-1α, E41X, causing a termination codon behind the dimerization domain, was found. The penetrance in individuals older than 25 years was 81.8%. The age at manifestation of diabetes ranged from 18 to 63 years, only 2 out of 10 diabetic individuals developed the disease at ages younger than 25 years. Although diabetes duration lasted up to 35 years in this family, only one family member suffered from diabetic complications. Additional polymorphisms in HNF-1α, I27L and S487N, were found in this pedigree. Despite its biological inactivity, S487N polymorphism led in combination with E41X to a significant earlier manifestation of diabetes, whereas I27L polymorphism or increased Body Mass Index (BMI) did not. In spite of the severe gene defect, which truncates the protein behind the dimerization domain, the phenotype of E41X was relatively benign without frequent diabetic complications.

I27L Polymorphism in hepatocyte nuclear factor-1α gene and type 2 diabetes mellitus: A meta-analysis of studies about orient population (Chinese and Japanese)

AimsThe aim of the study was to investigate the relationship between I27L variant of HNF-1α gene and type 2 diabetes mellitus (T2DM) in an/the oriental population. MethodsWe recruited 149 T2DM patients and 96 non-diabetes controls from China. The I27L polymorphism in HNF-1α gene was detected by PCR–RFLP analysis. A mete-analysis of previously published studies on I27L and T2DM of orient population and our new study was performed. Databases of MEDLINE, CBM, and the Cochrane Library (CD-ROM) were electronically searched from January 1980 to April 2008. Analysis was performed by RevMan 4.2 software which was downloaded from website of Cochrane collaboration. Results(1). The genotype distribution of I27L/exon1 polymorphism in the HNF-1α gene was in Hardy–Weinberg equilibrium (χ2=2.34, 0.05<P<0.1). The IL, LL genotype frequencies and L allelic frequency were slightly higher in T2DM group than in controls (0.52, 0.14 and 0.40 in T2DM vs. 0.49, 0.08 and 0.33 in controls), but the difference were not statistically significant, which indicated that 27L variant did not increase the risk of T2DM in our small sample Chinese population. (2). Three published studies concerning the Chinese population, two studies involving the Japanese population and our present study, providing information on a total of 1225 unique subjects, were included in the meta-analysis. The results showed that the 27L variant increased the prevalence of T2DM (OR 1.22, 95% CI 1.03–1.44, p=0.02). ConclusionI27L polymorphism in the HNF-1α gene increases the risk of T2DM in the orient population (Chinese and Japanese).

Identification of Novel Variants in the Hepatocyte Nuclear Factor-1α Gene in South Indian Patients with Maturity Onset Diabetes of Young

Mutations in the HNF 1A gene are the most common cause of maturity-onset diabetes of the young (MODY) in most populations. India currently has the largest number of people with diabetes in the world, and onset of type 2 diabetes occurs at a younger age with possible overlap with MODY. There are very few data on MODY mutations from India. The objective was to screen coding and promoter regions of HNF1A gene for mutations in unrelated South Indian subjects in whom a clinical diagnosis of MODY was made. This was an observational cross-sectional study. The study was conducted at a diabetes specialties centre in Chennai in southern India. Ninety-six unrelated south Indian subjects in whom clinical diagnosis of MODY was made were included in the study. The control population comprised of 57 unrelated nondiabetic subjects selected from the Chennai Urban Rural Epidemiology Study, a study conducted on a representative population (aged > or =20 yr) of Chennai. We identified nine novel variants comprising seven mutations (one novel mutation -538G>C at promoter region and six novel coding region mutations) and two polymorphisms in the HNF1A gene. Functional studies revealed reduced transcriptional activity of the HNF1A promoter for two promoter variants. We also observed cosegregation with diabetes of the Arg263His coding region mutation in eight members of one MODY family, whereas it was absent in nondiabetic subjects of this family. This study suggests that mutations in the HNF1A gene comprise about 9% of clinically diagnosed MODY subjects in southern India and a novel Arg263His mutation cosegregates with MODY in one family.

Estimating divergence times among subfamilies in Nymphalidae

The mitochondrial cytochrome oxidase subunit I (COI) gene and the nuclear elongation factor 1α (EF-1α) gene were sequenced from 13 species of Nymphalidae. Phylogenetic trees of Nymphalidae, which is the largest family in butterflies, were constructed based on the sequences determined from 13 species sequenced in our laboratory and an additional 43 species obtained from GenBank using the maximum likelihood (ML) and Bayesian methods. Relative-rate tests between lineages in these phylogenetic trees were performed. On the basis of the results of the relative-rate tests and fossil information of Satyrinae, Nymphalinae and Biblidinae, the average divergence times among the subfamilies are estimated as 44.2–87.1 million years ago (Ma). These results will be helpful for better understanding of the origin and evolution of this family, as well as the divergence time of butterflies and other complex taxa.

Phylogenetic relationship and morphological evolution in the subfamily Limenitidinae (Lepidoptera: Nymphalidae)

The mitochondrial cytochrome oxidase subunit I ( COI) gene and the nuclear elongation factor 1α ( EF-1α) gene were sequenced from 29 species of Nymphalidae (Nymphalidae, Lepidoptera). Phylogenetic trees were constructed based on the sequences determined from the 29 species and sequences of other 36 species deposited in GenBank using the neighbor-joining (NJ), maximum likelihood (ML) and Bayesian methods with Libythea celtis (Libytheinae) as the outgroup. Our phylogenetic trees indicated four major clades. Clade A includes three subfamilies: Apaturinae, Nymphalinae, and Limenitidinae, excluding the tribe Limenitidini; Clade B includes the subfamilies Heliconiinae and the tribe Limenitidini; Clade C includes Satyrinae, Calinaginae, Charaxinae and Morphinae; and Clade D includes subfamily Danainae. Our study suggested that the tribes Pseudergolini, Biblidini, Limenitidini and Cyrestidini should be considered as subfamilies and confirmed the interspecific relationships within the subfamily Pseudergolinae, namely Amnosia + ( Pseudergolis + ( Stibochiona + Dichorragia)). We then mapped three morphological characters (spot of anal angle, eyespots, and process from outer margin of hind wing) onto the phylogenetic tree constructed by ML analysis using the combined sequence data. Based on this the evolutionary patterns of these morphological characters were identified, they indicated that the three characters evolved repeatedly in the family Nymphalidae.

Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene

Previous studies have shown that hepatocyte nuclear factor-4alpha (HNF4alpha) is a central regulator of differentiated hepatocyte phenotype and forced expression of HNF4alpha could promote reversion of tumors toward a less invasive phenotype. However, the effect of HNF4alpha on cancer stem cells (CSCs) and the treatment of hepatocellular carcinoma (HCC) with HNF4alpha have not been reported. In this study, an adenovirus-mediated gene delivery system, which could efficiently transfer and express HNF4alpha, was generated to determine its effect on hepatoma cells (Hep3B and HepG2) in vitro and investigate the anti-tumor effect of HNF4alpha in mice. Our results demonstrated that forced re-expression of HNF4alpha induced the differentiation of hepatoma cells into hepatocytes, dramatically decreased "stemness" gene expression and the percentage of CD133(+) and CD90(+) cells, which are considered as cancer stem cells in HCC. Meanwhile, HNF4alpha reduced cell viability through inducing apparent apoptosis in Hep3B, while it induced cell cycle arrest and cellular senescence in HepG2. Moreover, infection of hepatoma cells by HNF4alpha abolished their tumorigenesis in mice. Most interestingly, systemic administration of adenovirus carrying the HNF4alpha gene protected mice from liver metastatic tumor formation, and intratumoral injection of HNF4alpha also displayed significant antitumor effects on transplanted tumor models. The striking suppression effect of HNF4alpha on tumorigenesis and tumor development is attained by inducing the differentiation of hepatoma cells--especially CSCs--into mature hepatocytes, suggesting that differentiation therapy with HNF4alpha may be an effective treatment for HCC patients. Our study also implies that differentiation therapy may present as one of the best strategies for cancer treatment through the induction of cell differentiation by key transcription factors.

Expression of HNF-4α (MODY1), HNF-1β (MODY5), and HNF-1α (MODY3) proteins in the developing mouse pancreas

The type 1, 3, and 5 forms of maturity-onset diabetes of the young (MODY) are caused by mutations of the genes encoding hepatocyte nuclear factor (HNF)-4α, HNF-1α, and HNF-1β, respectively [Yamagata, K., Oda, N., Kaisaki, P.J., Menzel, S., Furuta, H., Vaxillaire, M., et al., 1996a. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458; Yamagata, K., Furuta, H., Oda, N., Kaisaki, P.J., Menzel, S., Cox, N.J., et al., 1996b. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460; Horikawa, Y., Iwasaki, N., Hara, M., Furuta, H., Hinokio, Y., Cockburn, B.N. et al., 1997. Mutation in hepatocyte nuclear factor-1β gene (TCF2) associated with MODY. Nat. Genet. 17, 384–385]. Among these transcription factors, the pattern of HNF-4α expression during pancreatic differentiation remains largely unknown. We performed an immunohistochemical study to investigate its expression in comparison with the expression of HNF-1α and HNF-1β. We found considerable variation in the level of HNF-4α expression by the individual epithelial cells in the pancreatic buds on E9.5. HNF-4α and HNF-1β were initially expressed by Pdx1 + common progenitor cells and neurogenin3 + (Ngn3 +) endocrine precursor cells during the first transition, but expression of HNF-1β and either HNF-4α or HNF-1α became complementary around the end of the second transition (E15.5). In the mature pancreas, HNF-4α was expressed by glucagon-positive α-cells, insulin-positive β-cells, somatostatin-positive δ-cells, and pancreatic polypeptide-positive PP-cells, as well as by pancreatic exocrine cells and ductal cells. Most of the HNF-4α + cells were also positive for HNF-1α, but HNF-4α expression in some non-β-cells was remarkably high, and this was not paralleled by high HNF-1α expression. These results indicate that the expression of MODY proteins in each of the pancreatic cell types is strictly regulated in accordance with the status of differentiation during pancreatic organogenesis.

GAD Antibody in Multiplex Diabetic Pedigrees of Chinese

Multiplex diabetic families may be caused by mutations in genes of hepatocyte nuclear factors (maturity-onset diabetes of the young [MODY]1, -3, and -5), glucokinase (MODY2), insulin promoter factor-1 (MODY4), NeuroD1 (MODY6), mitochondrion ND1 and tRNALeu(UUR), and some other unknown genetic mutations. Recent studies showed that mutations of MODY are not common causes of diabetes in Chinese diabetic families (1–3), indicating that there may be other causes and mechanisms involved. Latent autoimmune diabetes in adults (LADA) shares some similar clinical phenotypes with MODY and is common in phenotypic type 2 diabetes (10–25%) (4). This study was conducted to investigate the distribution of GAD antibody (GADA) in multiplex diabetic pedigrees from the ChengDu area of China. A total of 140 family members of 18 families were recruited. In our previous study, most members had been screened for variants in mitochondrion ND1 and tRNALeu(UUR) and had been proved to be without deficiencies in these genes (5). Among them, 42 subjects in four families had been further screened in the hepatic nuclear factor-1α gene and had been found to have no suspected variant (T.C., Y.R., H.Y., X.Z., H.T., X. Cao, unpublished observations). Each family had three …

Association of genetic variations near P2 promoter of the hepatocyte nuclear factor-4α gene and insulin secretion index in Thais

This study was aimed to assess the association of the two single nucleotide polymorphisms (SNPs) near P2 promoter (rs1884614 and rs2144908) of hepatocyte nuclear factor-4alpha (HNF4A) with insulin secretion index and type 2 diabetes in Thais. Participants were categorized into three groups; unrelated type 2 diabetes (N = 219), prediabetes subjects (N = 228), and normal glucose tolerant controls (N = 203). Homeostasis model assessment was calculated for individual insulin secretion and insulin sensitivity index. Genotyping of both SNPs was done by allele-specific PCR technique. Difference of SNP allele frequencies between groups were computed using the chi (2)-statistic. Multivariate regression analysis was performed to determine the effect of SNPs on insulin secretion index. The clinical features of all groups were similar. We demonstrated genotype TT at rs1884614, BMI, and waist circumference were significantly associated with insulin secretion index (P = 0.023) but not with diabetes phenotype.

Etiology of Early-Onset Type 2 Diabetes in Indians: Islet Autoimmunity and Mutations in Hepatocyte Nuclear Factor 1α and Mitochondrial Gene

Indians are at high risk of developing type 2 diabetes mellitus (T2DM) at an early age, despite their lower body mass index. Studies on the etiology of patients presenting as early-onset T2DM in this racial group are not available. The objective was to delineate the clinical features in young Indian patients with T2DM and to determine the role of mutations in the hepatocyte nuclear factor 1alpha (HNF1alpha) gene [MODY3 (maturity-onset diabetes of the young, type 3)], mitochondrial A3243G mutation, and islet autoimmunity in its etiology. This was an observational cohort study. The setting was an outpatient diabetes clinic in a teaching hospital. Ninety-six consecutive young patients with T2DM (onset, <or=30 yr) were included in the study. Glutamic acid decarboxylase and insulinoma antigen 2 antibodies, mitochondrial A3243G mutation, and the common HNF1alpha mutation P291fsinsC were measured in all patients. The entire HNF1alpha gene was studied for mutations in 32 subjects with onset less than 25 yr or with normal weight. The common HNF1alpha A98V polymorphism was studied in 91 patients. The patients were clinically heterogeneous, with 42% having a normal body mass index. Glutamic acid decarboxylase antibodies were present in three (3%) subjects and mitochondrial A3243G mutation in one (1%) subject. The P291fsinsC mutation was not detected in any patient. A MODY3 mutation (R200W) was detected in one patient (3%). In this family, diabetes cosegregated with the R200W mutation in the proband and his youngest brother but not in three paternal uncles. The Val 98 allele was associated with T2DM (allele frequency, 0.14 vs. 0.03 in controls; odds ratio, 5.2; P < 0.001). Despite a significant proportion of young Indian patients with T2DM having normal weight, islet autoimmunity, A3243G mitochondrial, and HNF1alpha gene mutations were infrequent.