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

Congenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis caused by mutations in the steroid 21-hydroxylase gene (CYP21) in more than 90% of affected patients. The CYP21 gene is located within the HLA complex locus on chromosome 6 (6p21.3). During a molecular characterisation study of a group of 47 Mexican families with 21-hydroxylase deficiency, we identified nine in which the mutation or mutations found in the patient did not appear to originate from one of the parents. Through DNA fingerprinting, paternity was established in all nine families with a probability of non-paternity in the range of 10(-19) to 10(-23). Among these families, we identified one patient with exclusive paternal inheritance of all eight markers tested on chromosome 6p, despite normal maternal and paternal contributions for eight additional markers on three different chromosomes. We did not identify duplication of paternal information for markers in the 6q region, consistent with lack of expression of transient neonatal diabetes owing to genomic imprinting in this patient. Our results substantiate evidence for the existence of different genetic mechanisms involved in the expression of this recessive condition in a substantial portion (approximately 19%) of affected Mexican families. In addition to the identification of a patient with paternal uniparental disomy, the occurrence of germline mutations may explain the unusual pattern of segregation in the majority of the remaining eight families.
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PMID:Uniparental disomy for chromosome 6 results in steroid 21-hydroxylase deficiency: evidence of different genetic mechanisms involved in the production of the disease. 986 99

Of 957 patients with type 1 diabetes without known Addison's disease 1.6% (n = 15) were positive for 21-hydroxylase autoantibodies. Among DQ8/DQ2 heterozygous patients, the percentage expressing 21-hydroxylase autoantibodies was 5% (10 of 208) vs. less than 0.5% of patients with neither DQ8 nor DQ2. Three of the diabetic patients found to have 21-hydroxylase autoantibodies on screening were subsequently diagnosed with Addison's disease. Overall, the genotype DQ8/DQ2, consisting of DRB1*0404/DQ8 with DRB1*0301/DQ2, was present in 14 of 21 patients with Addison's disease (8 of 12 with diabetes and 6 of 9 without diabetes or antiislet autoantibodies) vs. 0.7% of the general population (109 of 15,547; P < 10(-6)) and 11% of patients with DM without Addison's disease (62 of 578; P < 10(-6)). Among patients with diabetes with DQ8, Addison's disease was strongly associated with the specific DRB1 subtype, DRB1*0404 (8 of 9 patients from 8 families, in contrast to only 109 of 408 DQ8 DM patients with diabetes without Addison's disease having DRB1*0404; P < 0.001). Among 21-hydroxylase autoantibody-positive DQ8 patients, 80% with DRB1*0404 (12 of 15) had Addison's disease, in contrast to 1 of 10 autoantibody-positive patients with DRB1*0401 or DRB1*0402 (P < 0.001). We conclude that patients with DRB1*0404 and 21-hydroxylase autoantibodies are at high risk for Addison's disease. Patients with DRB1*0401 and DRB1*0402 have more limited progression to Addison's disease despite the presence of 21-hydroxylase autoantibodies.
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PMID:DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease. 992 Jan 3

Idiopathic Addison's disease develops as a consequence of autoimmune destruction of steroid-producing cells in the adrenal gland. A major autoantigen is 21-hydroxylase (21OH; P450c21), which is involved in the biosynthesis of cortisol and aldosterone in the adrenal cortex. We selected a number of functionally important 21OH amino acid substitutions, found in patients with congenital adrenal hyperplasia, to study their effects on the binding of 21OH autoantibodies (21OHAb) to 21OH. The ability of 21OHAb to bind in vitro transcribed and translated wild-type 21OH and five different 21OH mutant proteins was quantified by liquid-phase assays. Sera from 21OHAb-positive patients with idiopathic Addison's disease (n = 24), Graves' disease (n = 3), and insulin-dependent diabetes mellitus (n = 1) were used. While the P105L, delE196, and G291S mutations had no effect on autoantibody binding, the P453S mutation had a considerable effect, and the R483P mutation almost completely abolished binding. Synthetic peptides corresponding to linear epitopes defined by amino acids 447-461 and 477-491 were unable to compete with wild-type 21OH for binding to autoantibodies. Direct 21OH DNA sequencing could not reveal any specific genetic variation in alleles found in 21OHAb-positive patients. We conclude that the region involving R483 plays a key role in the formation of a three-dimensional epitope in a functionally important C-terminal domain of the enzyme.
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PMID:A conformation-dependent epitope in Addison's disease and other endocrinological autoimmune diseases maps to a carboxyl-terminal functional domain of human steroid 21-hydroxylase. 997 24

Adrenal P450 enzymes 21-hydroxylase (21OH), 17alpha-hydroxylase (17OH) and side chain cleavage enzyme (SCC) represent major target antigens in adrenal autoimmunity. To evaluate the diagnostic sensitivity of autoantibodies to recombinant adrenal antigens we established rapid and sensitive radioligand assays and compared the results with adrenocortical autoantibodies (ACA) as detected by the standard immunofluorescence test. A high prevalence of antibodies to 21OH (21OH-A) was observed in patients with isolated Addison's disease (IAD) and patients suffering from autoimmune polyendocrine syndrome type II (APS II). 21OH-A were found in 19 of 25 (76%) patients with IAD and in 34 of 40 (85%) patients with APS II. In contrast, antibodies to 17OH (17OH-A) as well as antibodies to SCC (SCC-A) were detected in 12 (30%) and 13 (33%) patients with APS II whereas only a few sera from patients with IAD had 17OH antibodies (n = 3) and SCC-A (n = 1), respectively (p < 0.0001). The majority of patients with 17OH-A (83.3%) or SCC-A (76.9%) were also found positive for 21OH-A and all three antibody specificities were positively correlated with the presence of ACA. Among 52 sera with ACA 49 (94.2%), 11 (21.2%), and 9 (17.3%) were positive for 21OH-A, 17OH-A and SCC-A, respectively. By combination of 21OH-A with 17OH-A all ACA positive individuals were identified. The availability of recombinant steroid P450 enzymes made it possible to develop radiobinding assays which allow simple, sensitive and quantitative detection of autoantibodies to defined adrenal autoantigens. We here demonstrate that autoantibodies to 21-hydroxylase are sensitive markers for autoimmune Addison's disease with and without polyglandular failure. The presence of 17OH-A or SCC-A may suggest the coexistence of or progression towards polyglandular autoimmunity.
Exp Clin Endocrinol Diabetes 1999
PMID:Autoantibodies to adrenal cytochrome P450 antigens in isolated Addison's disease and autoimmune polyendocrine syndrome type II. 1037 48

Autoantibodies against aromatic L-amino acid decarboxylase (AADC) are present in about 50 percent of sera from patients with autoimmune polyendocrine syndrome type I (APS I) but absent in sera from patients with different organ-specific autoimmune diseases, such as insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, and Graves' disease. AADC is expressed in the pancreatic beta-cells, the liver, and the nervous system; and the presence of AADC antibodies has been shown to correlate to hepatitis and vitiligo in APS I patients. Among 101 investigated patients with autoimmune Addison's disease, 15 had high titers of AADC antibodies. According to the clinical characteristics of these patients, only 3 had APS I. The remaining 12 had either isolated Addison's disease or associated diabetes mellitus, hypothyroidism, vitiligo, alopecia, gonadal failure, and pernicious anemia. Autoantibodies against 21-hydroxylase were present in 9 of 12, whereas autoantibodies against side-chain cleavage enzyme and 17alpha-hydroxylase were present in 3 of 12. Two patients had only autoantibodies against AADC. DNA was available from 3 of these 12 patients. One of the patients, a woman with Addison's disease, autoimmune thyroiditis, and premature menopause was heterozygous for a point mutation (G1021A, Val301Met) in the first plant homeodomain zinc finger domain of the autoimmune regulator (AIRE) gene. The presence of AADC autoantibodies identifies patients with APS I and a subgroup of Addison patients who may have a milder atypical form of APS I or represent a distinct entity. Measurement of autoantibodies against AADC should be included in the evaluation of Addison's disease.
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PMID:Autoantibodies against aromatic L-amino acid decarboxylase identifies a subgroup of patients with Addison's disease. 1063 24

Sera from 300 Italian patients with Addison's disease were collected over a 30 year period. Among these patients, 82% had autoimmune disease, 13% had tuberculosis and 5% had another causal condition. In 59% of the cases, autoimmune disease was associated with the autoimmune manifestations contributing to the description of polyglandular autoimmune disease (PGAD). In PGAD type 1, the disease was associated with chronic candidiasis and/or chronic hypoparathyroidism. In PGAD type 2, the patients had autoimmune thyroid disease and/or diabetes mellitus type 1, and in PGAD type 4, they presented a combination with other autoimmune diseases excluding those previously mentioned. Finally, the autoimmune disease was apparently isolated in 41% of the cases. In addition, patients with these four forms of disease exhibited a different genetic pattern, sex distribution, and age at presentation in addition to minor frequency of autoimmune diseases. Adrenal cortex autoantibodies directed against 21-hydroxylase were common serological markers for these four main clinical forms, showing a very high frequency at clinical onset of adrenal insufficiency. In some patients, steroid-producing cell autoantibodies were also present and correlated with gonadal failure and they recognize of 17alpha-hydroxylase or P450 side chain cleavage enzymes as target antigens.
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PMID:Autoimmunity in isolated Addison's disease and in polyglandular autoimmune diseases type 1, 2 and 4. 1135 94

In Latvia diabetes mellitus is diagnosed using the WHO's clinical criteria; assays for the detection of autoantibodies are not available, and hence slowly progressive autoimmune diabetes is likely to be missed. Autoantibodies against glutamic acid decarboxylase (GAD65) and protein tyrosine phosphatase (IA-2) among patients with clinically diagnosed NIDDM identify group of patients with slow-onset type 1 diabetes or LADA. The aim of this study was to estimate the risk of polyendocrine autoimmunity among clinically diagnosed NIDDM patients from Latvia. One hundred NIDDM patients and 100 healthy controls were tested for GAD65 and IA-2 autoantibodies as well as 21-hydroxylase (21-OH) and tissue transglutaminase (TTG) antibodies by RIA assay. Age at onset was >or= 30 years, and duration of disease less than 5 years. Of 100 patients, 85 were on oral hypoglycemic agents and 15 were on insulin. Body mass index (BMI) under 19 was recorded in 1% (1 of 100 cases), while overweight (BMI > 25.5 in females and 27 in males) was documented in 45% (45 of 100 cases). GAD65 antibodies were found in 30 of 100 (30%) and IA-2 antibodies in 40 of 100 (40%) patients. Either GAD65 or IA-2 antibodies were found in 55 of 100 (55%). None of the patients carried antibodies against 21-OH and only 1 of 100 (1%) carried antibodies against TTG. From the results obtained in our study we conclude that in Latvian adult NIDDM subjects, islet autoantibodies identify groups of slow-onset type 1 diabetes but not polyendocrine autoimmunity.
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PMID:Islet autoantibodies in Latvian subjects with non-insulin-dependent diabetes mellitus: slow-onset type 1 diabetes or polyendocrine autoimmunity? 1202 Nov 19

Women with gestational diabetes mellitus (GDM) have considerable risk for developing both type 1 and type 2 diabetes in life. Autoantibodies against glutamic acid decarboxylase (GAD65) and tyrosine phosphatase (IA-2) are strongly associated with autoimmune diabetes and can be useful in early identification of the development of type 1 diabetes in women with GDM. On the other hand antibodies against minor islet antigens in adults can be predictors for autoimmune polyendocrine syndrome. The aim of our study was to estimate the prevalence of autoantibodies against minor antigens-tissue transglutaminase (TTG), ICA12, and 21-hydroxylase (21-0H)-in GDM patients from southern India. Eighty-six serum samples from GDM subjects and 114 samples from healthy controls were tested for the presence of GAD65 and IA-2Ab as well as for the presence of 21-OH, TTG, and ICA12Ab by radiobinding assay with in vitro translated recombinant human 35S-GAD65, IA-2, TTG, ICA12, and 21-OH antigens. We observed the presence of GAD65 or IA-2 autoantibodies in 41% (35/86) of GDM patients, while none of the patients tested positive for any of the minor autoantibodies. Our results demonstrate that there is a high prevalence of autoantibodies in GDM subjects that are at higher risk of developing autoimmune diabetes later, but none of the patients carries antibodies against minor antigens, which could predict autoimmune polyendocrine syndrome in adults.
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PMID:Women diagnosed with gestational diabetes mellitus do not carry antibodies against minor islet cell antigens. 1202 Nov 24

Genetic defects in genes encoding hormones, hormone receptors or polypeptides of the signaling pathways usually cause complex disease manifestations characterized by the involvement of several tissues and variable expression. Genetic aberrations, like chromosome aneuploidy, gene translocations or mutations in key regulatory proteins (even if not directly affecting genes of the endocrine system) often lead to clinical symptoms, including central endocrine functions like sexual differentiation or metabolic disturbances, like diabetes mellitus. But also minor genetic alterations like point mutations can affect the function of gene products to cause endocrine diseases. If the underlying molecular defects of endocrinopathies are known, direct molecular diagnosis can be performed. This is particularly useful if it helps to solve difficult differential diagnosis problems or if there exist effective preventive therapeutic options. The present paper presents examples for endocrine diseases in which molecular testing significantly increases the specificity and sensitivity of diagnostics and demonstrates the benefits for the patients and the healthcare system. In multiple endocrine neoplasia type 2, an unambiguous identification of gene carriers in affected families can be achieved by genetic testing. As a preventive measure to avoid medullary thyroid carcinoma, prophylactic thyroidectomy is recommended for individuals carrying the disease causing mutation. In adrenogenital syndrome, sequence analysis of the steroid 21-hydroxylase gene has become an important tool to confirm or exclude suspected late-onset forms of the disease, where hormone measurements are not informative. The major benefit, however, lies in identifying heterozygous carriers and providing a reliable prenatal test for couples carrying a defect in the 21-hydroxylase gene. Today, prenatal treatment with dexamethasone, which prevents the virilization in female fetuses, should always be based on results from molecular diagnosis performed from chorionic villus samples.
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PMID:Clinical impact of molecular diagnostics in endocrinology. Polymorphisms, mutations and DNA technologies. 1243 89

Hirsutism is the presence of terminal (coarse) hairs in females in a male-like pattern, affecting between 5% and 15% of women, depending on definition. Hirsutism has a significant negative impact on psychosocial development and is usually a sign of an underlying endocrine abnormality-namely, androgen excess. The most common cause of androgen excess is the polycystic ovary syndrome (PCOS), with 21-hydroxylase-deficient nonclassic adrenal hyperplasia, the hyperandrogenic insulin-resistant acanthosis nigricans syndrome, androgen-secreting tumors, and androgenic drug intake occurring less frequently. However, although 70-80% of patients with androgen excess demonstrate hirsutism, this sign may be less prevalent among women of Asian extraction. Conversely, not all hirsute patients have evidence of detectable androgen excess, as 5-15% of these women have "idiopathic hirsutism," with normal ovulatory function and androgen levels. There is a strong familial predilection for hirsutism, primarily because the underlying endocrine disorders (eg, PCOS) and the factors regulating the development of hair growth (eg, androgen receptor activity, 5alpha-reductase activity) have a strong genetic component. The diagnostic evaluation of the potentially hirsute patient first involves confirming the presence of hirsutism and then excluding associated or etiological abnormalities and disorders (eg, ovulatory dysfunction, adrenal hyperplasia, diabetes, thyroid hormone abnormalities). Treatment should be undertaken using combination therapy, to possibly include 1) hormonal suppression (oral contraceptives, long-acting gonadotropin-releasing hormone analogues, and insulin sensitizers), 2) peripheral androgen blockade (spironolactone, flutamide, cyproterone acetate, or finasteride), and 3) mechanical/cosmetic amelioration and destruction of the unwanted hairs (electrology and, potentially, laser hair removal). The application of eflornithine hydrochloride 13.9% topical cream may also be useful to ameliorate unwanted facial hair growth. Overall, although hirsutism is a frequent and distressing abnormality often signaling an underlying endocrine disorder, a systematic approach to evaluation will uncover the etiology, and combination therapy will provide satisfactory treatment for most patients.
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PMID:The evaluation and management of hirsutism. 1273 63


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