A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome
| العنوان: | A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome |
|---|---|
| المؤلفون: | Anu Guthikonda, Michael L. Metzker, Dena L. Mansouri, Mario Maldonado, Ashok Balasubramanyam, Dinakar Iyer, Ramaswami Nalini, Wade C. Haaland, Christiane S. Hampe, Sanjeet G. Patel, Diane I. Scaduto |
| المصدر: | Diabetes Care |
| بيانات النشر: | American Diabetes Association, 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Adult, Male, medicine.medical_specialty, Diabetic ketoacidosis, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Islets of Langerhans, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, Glucokinase, Basic Helix-Loop-Helix Transcription Factors, Internal Medicine, medicine, Humans, Insulin, Paired Box Transcription Factors, Family history, Pathophysiology/Complications, Autoantibodies, Hepatocyte Nuclear Factor 1-beta, Original Research, Glycated Hemoglobin, Homeodomain Proteins, Advanced and Specialized Nursing, business.industry, Genetic Variation, Middle Aged, medicine.disease, HNF1B, HNF1A, Diabetes Mellitus, Type 1, Endocrinology, Diabetes Mellitus, Type 2, Hepatocyte Nuclear Factor 4, NEUROD1, Trans-Activators, Female, business, Ketosis-prone diabetes |
| الوصف: | OBJECTIVE Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A−β− subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes. RESEARCH DESIGN AND METHODS Over 8 years, 37 patients with an A−β− phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects. RESULTS The majority (70%) of the A−β− KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′–untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported. CONCLUSIONS Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated β-cell dysfunction, A−β− KPD is most likely not a predominantly monogenic diabetic syndrome. Several A−β− KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology. |
| تدمد: | 1935-5548 0149-5992 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0cea787e00f7727fcaf5cc76511cdc65Test https://doi.org/10.2337/dc08-1529Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0cea787e00f7727fcaf5cc76511cdc65 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19355548 01495992 |
|---|