Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An A to G transition at nucleotide 3,243 in the tRNA(Leu(UUR)) gene of mitochondrial DNA (mtDNA) has been suggested to be the disease-related mutation for MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Recently, the same mutation has also been found in several pedigrees with maternally inherited diabetes mellitus and sensorineural deafness. We report here a family showing the association of deafness and diabetes mellitus, as the predominant clinical features, with this mutation. The mutation was detected by restriction-enzyme analysis of the relevant PCR-amplified segment of the mtDNA, in two generations. In this family, it is noteworthy that two members with the mutation had some symptoms of MELAS such as short stature, seizures and mental retardation and that one had no clinical symptoms though the mtDNA mutation was identified in his blood. The findings in this family demonstrate the diversity of clinical expression of the mtDNA mutation and suggest that a combination of sensorineural deafness and diabetes mellitus is only one typical presentation of the various phenotypic features caused by the 3,243 mutation.
 ...
PMID:[Detection of a mutation in mitochondrial DNA in a family with sensorineural deafness and diabetes mellitus as the predominant clinical features]. 756 31

As a result of advances in technology, genome searches have been carried out for susceptibility genes for type 1 diabetes in humans and in the NOD mouse. These have shown that, in the NOD mouse, diabetes susceptibility is under the control of at least ten separate chromosomal loci. In the human, in addition to HLA and INS, two new susceptibility genes have been localized, IDDM4 on chromosome 11q and IDDM5 on 6q, demonstrating the polygenic nature of type 1 diabetes and the role of HLA as the major locus. Candidate genes at these loci are the subject of current investigation. Genetic and immunological markers of disease may be of value in screening the general population for individuals at risk of developing type 1 diabetes. The predictive power of different screening strategies should be tested in order to work out the potential value to the general population of preventive therapies that are now undergoing clinical trials in high risk 'pre-diabetics'. Type 2 diabetes is genetically heterogeneous, and, since 1992, two distinct genetic subtypes have been identified. The first is defined by mutations in the GCK gene, which cause up to 60% of cases of MODY. The second, designated MIDD (maternally inherited diabetes and deafness), is defined by mutation in the mitochondrial gene for tRNA(Leu(UUR)). MIDD patients are less obese than is usual for typical type 2 diabetes, may present in early adult life or occasionally in childhood and may have been diagnosed as having autoimmune type 1 diabetes, type 2 diabetes or MODY. Typically, patients with MIDD require insulin earlier than do type 2 diabetics without mitochondrial mutations. Genetically complex diseases, such as diabetes, hypertension, cancer and coronary heart disease, are common in most populations. The approaches to the genetic analysis of diabetes outlined in this review are likely to be useful to the genetic analysis of many of these disorders. Progress in this area will have important implications for public health strategies in the next decade and beyond.
 ...
PMID:Molecular genetics of diabetes mellitus. 757 35

We review the relationship between various types of mitochondrial DNA mutations and the prevalence as well as the pathobiochemical and clinical features of mitochondrial diabetes mellitus. An A to G transversion mutation in the tRNA(Leu(UUR)) gene is associated with diabetes in about 1.5% of the diabetic population in different countries and races. Phenotypically this type of mitochondrial diabetes is combined with deafness in more than 60% and is clinically distinguishable with respect to several characteristics from the two idiopathic forms of diabetes. The underlying pathomechanism is probably a delayed insulin secretion due to an impaired mitochondrial ATP production in consequence of the mtDNA defect.
 ...
PMID:Mitochondrial diabetes mellitus: a review. 759 17

We have recently described a mitochondrial DNA (mtDNA) point mutation at np 3243 in the tRNA(Leu)(UUR) gene in a large Dutch pedigree with maternally inherited diabetes mellitus and deafness (MIDD) illustrating the importance of mitochondrial function in maintenance of a proper glucose homeostasis. In this review we will focus on the prevalence of the mtDNA mutation at np 3243 in diabetic populations, as well as postulate some working models for its pathogenicity.
 ...
PMID:Maternally inherited diabetes and deafness (MIDD): a distinct subtype of diabetes associated with a mitochondrial tRNA(Leu)(UUR) gene point mutation. 760 13

Japanese diabetic patients whose mothers were also diabetic were screened, using peripheral leukocytes, for an A to G transition at nucleotide pair 3243 of the mitochondrial gene, a tRNA(Leu)(UUR) mutation. This mutation was identified in four pedigrees from among 300 unrelated patients. Diabetes mellitus cosegretated with the mutation, except in 1 young subject, and was maternally inherited. Long-term follow-up revealed that the underlying disorder in affected members is a progressive impairment of insulin secretion. In accord with this finding, this mutation was found to be highly prevalent in a subset of diabetes mellitus called slowly progressive IDDM; the mutation was identified in 3 of 27 Japanese patients enrolled in the prospective study of islet cell antibody (ICA)-positive, initially non-insulin-dependent diabetic patients, who are very likely to become insulin dependent in several years. The histologic characteristics of slowly progressive IDDM include loss, though incomplete, of pancreatic beta-cells. Mitochondrial gene defects in beta-cells could therefore cause glucose-induced signaling defects as well as beta-cell loss, which explains the wide range of diabetic phenotypes, from NIDDM phenotype to IDDM, in patients with this mitochondrial gene mutation.
 ...
PMID:Mitochondrial diabetes mellitus--glucose-induced signaling defects and beta-cell loss. 760 14

More than half of the Pima Indians over age 35 years have non-insulin-dependent (type II) diabetes mellitus (NIDDM). Extensive data indicate the importance of maternal diabetes in determining their risk for diabetes. Generally, the risk of having NIDDM is higher in patients with affected mothers than affected fathers. This has been attributed to intrauterine factors, but recently mitochondrial inheritance has been raised as an alternative hypothesis. In other populations, several families and individuals with diabetes due to a mitochondrial DNA point mutation at nucleotide 3243 in the tRNA(leu(UUR)) gene have been described, as has one family with a 10.4 kb mitochondrial DNA duplication/deletion. We tested whether these specific mitochondrial gene mutations could explain a portion of the excess maternal transmission seen in the Pima Indians. Mitochondrial DNA obtained from blood lymphocytes of 148 Pima Indians with NIDDM was screened both for the point mutation at nt 3243, and the 10.4 kb duplication/deletion. Neither of these mutations was detected, and although a small proportion of the excess maternal transmission in Pima Indians could still be due to yet undescribed mitochondrial mutations or imprinted nuclear genes, our data support the role of the intrauterine environment in this population.
 ...
PMID:Screening for mtDNA diabetes mutations in Pima Indians with NIDDM. 762 45

We studied 22 subjects carrying the A3243G point mutation of human mitochondrial DNA (mtDNA). In 14 cases the clinical phenotype was characterized by mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), while 8 patients had chronic progressive external ophthalmoplegia (CPEO). The proportion of A3243G heteroplasmy in muscle was determined by two methods; densitometry on a diagnostic restriction-fragment length polymorphism and solid-phase mini-sequencing. We found a highly significant inverse correlation between the percentage of A3243G mutation and the specific activity of complex I, the respiratory complex with the highest number of mtDNA-encoded subunits, suggesting a direct effect of the mutation on mtDNA translation. No correlation was observed between the percentage of mutated mtDNA and the presence or absence of specific clinical features, such as stroke, ophthalmoplegia and diabetes mellitus. However, in the MELAS group the percentage of mutated mtDNA molecules was strongly correlated with the age of onset, while no such correlation was found in the CPEO group, suggesting a different time-dependent evolution of the mutation in the two groups. Finally, in contrast with other mtDNA mutations associated with ragged-red fibres (RRF), in both MELAS3243 and CPEO3243 we observed a high proportion of RRF that were positive to the histochemical reaction to cytochrome c oxidase, a morphological feature that seems to be specific for the neuromuscular phenotypes associated with mutations affecting the tRNA(Leu(UUR)) gene.
 ...
PMID:Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3243G mutation of mitochondrial DNA. 764 39

We screened 214 Japanese NIDDM (non-insulin-dependent) diabetic patients with a family history of diabetes for mutations in the mitochondrial tRNA(Leu(UUR)) gene using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Six patients were identified as having an A to G transition at position 3243 (3243 mutation), but no patients were detected with a T to C transition at position 3271, in the mitochondrial tRNA(Leu(UUR)) gene. These two mutations were not present in 85 healthy control subjects. It was disclosed that the patients' mothers were also affected by diabetes mellitus in five of the six cases. In these six affected patients, the 3243 mutation shows variable phenotypes, such as the degree of multiple organ involvement, intrafamilial and interfamilial differences in disease characteristics, and the degree of the involvement of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) phenotype. Endocrinological examinations revealed that those diabetic patients with the 3243 mutation show not only beta-cell dysfunction, but also a defect in alpha-cell function, which is considered characteristic of diabetes with the 3243 mutation. When compared with 50 selected diabetic control subjects without the 3243 mutation, whose mothers, but not fathers, were found to have diabetes, it was established statistically that those with the 3243 mutation possess the following clinical characteristics; 1) the age of diabetes onset is lower, 2) they have lean body constitutions, and 3) they are more likely to be treated with insulin than control subjects. We suggest that diabetes with the 3243 mutation possesses phenotypes distinct from those in common forms of diabetes.
 ...
PMID:Diabetes mellitus carrying a mutation in the mitochondrial tRNA(Leu(UUR)) gene. 926 98

We have identified a novel mtDNA mutation in a 29-year-old man with myopathy and diabetes mellitus. This T-->C transition at mtDNA position 14709 alters an evolutionarily conserved nucleotide in the region specifying for the anticodon loop of the mitochondrial tRNA(Glu). The nt-14709 mutation was heteroplasmic but present at very high levels in the patient's muscle, white blood cells (WBCs), and hair follicles; lower proportions of mutated mtDNA were observed in WBCs and hair follicles of all examined maternal relatives. In the patient's muscle, abnormal fibers showed mitochondrial proliferation, severe focal defects in cytochrome c oxidase activity, and absence of cross-reacting material for mitochondrially synthesized polypeptides. These fibers had higher levels of mutated mtDNA than did surrounding "normal" fibers. Although the percentage of mutated mtDNA in WBCs from family members were distributed around the percentage observed in the mothers, the pattern was different in hair follicles, where the mutated population tended to increase in subsequent generations. PCR/RFLP analysis of single hairs showed that the intercellular variations in the percentage of mutated mtDNA differed among family members, with younger generations having a more homogeneous distribution of mutated mtDNA in different hair follicles. These results suggest that the intercellular distribution of the mutated and wild-type mtDNA populations may drift toward homogeneity in subsequent generations.
 ...
PMID:Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. 772 54

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.
 ...
PMID:Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation. 772 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>