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

• Published in: Diabetologia 2008-05, Vol.51 (5), p.802-810
• Main Authors: Tammaro, P, Flanagan, S. E, Zadek, B, Srinivasan, S, Woodhead, H, Hameed, S, Klimes, I, Hattersley, A. T, Ellard, S, Ashcroft, F. M
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Adenosine Triphosphate - pharmacology; Adult; Amino Acid Substitution; Animals; Biological and medical sciences; Child; Child, Preschool; Diabetes Mellitus - drug therapy; Diabetes Mellitus - genetics; Diabetes. Impaired glucose tolerance; DNA - blood; DNA - genetics; DNA - isolation & purification; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glycated Hemoglobin - analysis; Human Physiology; Humans; Hypoglycemic Agents - therapeutic use; Infant, Newborn; Infant, Newborn, Diseases - genetics; Internal Medicine; KATP channel; KCNJ11; Kir6.2; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Models, Molecular; Mutation; Neonatal diabetes; noninsulin-dependent diabetes mellitus; Oocytes - physiology; Potassium Channels, Inwardly Rectifying - chemistry; Potassium Channels, Inwardly Rectifying - drug effects; Potassium Channels, Inwardly Rectifying - genetics; Protein Conformation; Sulfonylurea Compounds - therapeutic use; Xenopus; Xenopus laevis
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-008-0923-1

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 KATP 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.