A Kir6.2 mutation causing severe functional effects in vitro produces neonatal diabetes without the expected neurological complications

التفاصيل البيبلوغرافية
العنوان: A Kir6.2 mutation causing severe functional effects in vitro produces neonatal diabetes without the expected neurological complications
المؤلفون: Helen J Woodhead, S. Srinivasan, Paolo Tammaro, Frances M. Ashcroft, Sian Ellard, Iwar Klimes, Andrew T. Hattersley, Shihab Hameed, Brittany Zadek, Sarah E. Flanagan
المصدر: Diabetologia
بيانات النشر: Springer Nature
مصطلحات موضوعية: Models, Molecular, Kir6.2, Protein Conformation, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, medicine.disease_cause, Infant, Newborn, Diseases, Xenopus laevis, chemistry.chemical_compound, Epilepsy, Adenosine Triphosphate, 0302 clinical medicine, KCNJ11, Child, 0303 health sciences, Mutation, KATP channel, Permanent neonatal diabetes mellitus, 3. Good health, Child, Preschool, Female, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Biology, Article, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Diabetes Mellitus, medicine, Internal Medicine, Animals, Humans, Hypoglycemic Agents, Potassium Channels, Inwardly Rectifying, 030304 developmental biology, Glycated Hemoglobin, Infant, Newborn, Neonatal diabetes, DNA, medicine.disease, Sulfonylurea Compounds, Endocrinology, Amino Acid Substitution, chemistry, Oocytes, Complication, Adenosine triphosphate
الوصف: AIMS/HYPOTHESIS: Heterozygous activating mutations in the pancreatic ATP-sensitive K+ channel cause permanent neonatal diabetes mellitus (PNDM). This results from a decrease in the ability of ATP to close the channel, which thereby suppresses insulin secretion. PNDM mutations that cause a severe reduction in ATP inhibition may produce additional symptoms such as developmental delay and epilepsy. We identified a heterozygous mutation (L164P) in the pore-forming (Kir6.2) subunit of the channel in three unrelated patients and examined its functional effects. METHODS: The patients (currently aged 2, 8 and 20 years) developed diabetes shortly after birth. The two younger patients attempted transfer to sulfonylurea therapy but were unsuccessful (up to 1.1 mg kg(-1) day(-1)). They remain insulin dependent. None of the patients displayed neurological symptoms. Functional properties of wild-type and mutant channels were examined by electrophysiology in Xenopus oocytes. RESULTS: Heterozygous (het) and homozygous L164P K(ATP) channels showed a marked reduction in channel inhibition by ATP. Consistent with its predicted location within the pore, L164P enhanced the channel open state, which explains the reduction in ATP sensitivity. HetL164P currents exhibited greatly increased whole-cell currents that were unaffected by sulfonylureas. This explains the inability of sulfonylureas to ameliorate the diabetes of affected patients. CONCLUSIONS/INTERPRETATION: Our results provide the first demonstration that mutations such as L164P, which produce a severe reduction in ATP sensitivity, do not inevitably cause developmental delay or neurological problems. However, the neonatal diabetes of these patients is unresponsive to sulfonylurea therapy. Functional analysis of PNDM mutations can predict the sulfonylurea response.
اللغة: English
تدمد: 0012-186X
DOI: 10.1007/s00125-008-0923-1
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0c745dfb288cfb29052310287e0f15ccTest
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....0c745dfb288cfb29052310287e0f15cc
قاعدة البيانات: OpenAIRE
الوصف
تدمد:0012186X
DOI:10.1007/s00125-008-0923-1