The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene.
Mutations in several genes encoding transcription factors of the hepatocyte nuclear factor (HNF) cascade are associated with maturity-onset diabetes of the young (MODY), a monogenic form of early-onset diabetes mellitus. The ability of the orphan nuclear receptor small heterodimer partner (SHP, NR0B2) to modulate the transcriptional activity of MODY1 protein, the nuclear receptor HNF-4␣, suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with earlyonset diabetes for mutations in this gene and found five different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, and R213C) in 6 subjects as well as one apparent polymorphism (R216H), all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with diabetes. Therefore, an additional group of 101 unrelated nondiabetic subjects with early-onset obesity was screened for mutations in the SHP gene. Two of the previously observed mutations (R34X and A195S) and two additional mutations (R57W and G189E) were identified in 6 subjects, whereas no mutations were identified in 116 young nondiabetic lean controls (P ؍ 0.0094). Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight and reveal a pathway leading to this common metabolic disorder in Japanese.nuclear receptor ͉ maturity-onset diabetes of the young ͉ insulin secretion ͉ body weight ͉ hepatocyte nuclear factor H eterozygous mutations in genes encoding transcription factors in the hepatocyte nuclear factor (HNF) regulatory cascade (1) are associated with an early-onset autosomal dominant form of diabetes mellitus, maturity-onset diabetes of the young (MODY) (2). To date, diabetes-associated mutations have been found in three members of this regulatory network, HNF-1␣, -1, and -4␣ (MODY3, 5, and 1, respectively) (3-6). These forms of MODY are characterized primarily by defective insulin secretion with normal body weight (7-9). In contrast, forms of early-onset autosomal-dominant type 2 diabetes that are not linked to known MODY genes are often characterized by insulin resistance with high body weight, rather than by pure pancreatic -cell defects (10). It is not known whether obesity-associated MODY genes or other common modifying factors are responsible for these phenotypic features.The protein small heterodimer partner (SHP; also called NROB2 for nuclear receptor subfamily 0, group B, member 2), an atypical orphan nuclear receptor that lacks a conventional DNA-binding domain, interacts with a number of other nuclear receptors, including HNF-4␣, and inhibits their transcriptional activity (11)(12)(13)(14)(15)(16)(17). SHP is expressed in the liver and has recently been suggested to regulate cholesterol homeostasis by an inhibitory e...
Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors. We recently reported that mutations in the SHP gene are associated with insulin resistance. In the present study, we demonstrated that the SHP gene is expressed in adipose tissues. A reporter gene assay showed that a gene product of SHP increased the transcriptional activation of peroxisome proliferator-activated receptor (PPAR) ␥. SHP-mediated activation of PPAR␥ was observed both in the presence and absence of the ligand of PPAR␥. Immunoprecipitation and glutathione S-transferase pull-down assay showed that SHP directly bound to PPAR␥ and competed with nuclear receptor corepressor for binding to PPAR␥. Serial deletion studies indicated that the C terminus of SHP is important for PPAR␥ activation. Mutant SHP proteins, which are found in naturally occurring mutation, showed less enhancing activity for PPAR␥ than wild-type SHP. Our results suggest that SHP may act as an endogenous enhancer of PPAR␥.The nuclear receptor superfamily is a group of transcription factors that regulate target genes in response to small lipophilic compounds such as steroids, thyroid hormone, and retinoids (1-4). In general, these nuclear receptors consist of several functional domains: an N-terminal ligand-independent transactivation domain (AF-1 1 ), a DNA-binding domain (DBD) that contains two zinc fingers, a hinge domain that is a variable linker region and a functionally complex C-terminal region that includes the ligand-binding domain, the dimerization interface, and the ligand-dependent transactivation domain (AF-2) (1-4). These nuclear receptors regulate expression of genes that function in a variety of metabolic pathways. Peroxisome proliferator-activated receptor (PPAR) ␥ is a transcription factor, belonging to the nuclear receptor superfamily. PPAR␥ is a master regulator for adipocyte differentiation (5, 6) and is important in regulation of a number of genes involved in fatty acid and glucose metabolism (7-9). Synthetic PPAR␥ ligands, thiazolidinedione drugs, increase insulin sensitivity and are used in the treatment of diabetic patients (10 -12). In contrast, individuals with a loss-of-function mutation in the PPAR␥ gene developed early-onset type 2 diabetes with severe insulin resistance (13). Therefore, endogenous modulators of PPAR␥ should affect the insulin sensitivity.Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor composed of 257 amino acids (human protein) or 260 amino acids (murine protein) that lacks a conventional DBD (14). It has been reported that SHP interacts with several other nuclear receptors and modulates the transcriptional activities (14 -19). Recently we reported that mutations in SHP gene in humans associated with insulin resistance and mild obesity (19). The underlying mechanism by which mutations in SHP gene represented such phenotypes has been unclear. We hypothesized that SHP might affect the transcriptional activation...
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