A new familial form of a late-onset, persistent hyperinsulinemic hypoglycemia of infancy caused by a novel mutation in KCNJ11
| Autor: | Roger K. Long, Christine T. Ferrara, Stephen E. Gitelman, Michael S. German, Shi-Bing Yang, Yen-Yu Yang |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty endocrine system ATP-Sensitive Potassium Channel (KATP) Potassium Channels medicine.medical_treatment Protein subunit Biophysics Late onset medicine.disease_cause Biochemistry 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Humans Potassium Channels Inwardly Rectifying Hyperinsulinemic hypoglycemia Receptor Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) sulphonylurea Receptor 1 (SUR1) business.industry Point mutation ER retention Potassium channel 3. Good health Inwardly Rectifying 030104 developmental biology Endocrinology Pancreatectomy Mutation Congenital Hyperinsulinism Inwardly Rectifying Potassium Channel 6.2 (Kir6.2) business 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Channels, vol 11, iss 6 Channels |
| Popis: | The ATP-sensitive potassium channel (KATP) functions as a metabo-electric transducer in regulating insulin secretion from pancreatic β-cells. The pancreatic KATP channel is composed of a pore-forming inwardly-rectifying potassium channel, Kir6.2, and a regulatory subunit, sulphonylurea receptor 1 (SUR1). Loss-of-function mutations in either subunit often lead to the development of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). PHHI is a rare genetic disease and most patients present with immediate onset within the first few days after birth. In this study, we report an unusual form of PHHI, in which the index patient developed hyperinsulinemic hypoglycemia after 1 year of age. The patient failed to respond to routine medication for PHHI and underwent a complete pancreatectomy. Genotyping of the index patient and his immediate family members showed that the patient and other family members with hypoglycemic episodes carried a heterozygous novel mutation in KCNJ11 (C83T), which encodes Kir6.2 (A28V). Electrophysiological and cell biological experiments revealed that A28V hKir6.2 is a dominant-negative, loss-of-function mutation and that KATP channels carrying this mutation failed to reach the cell surface. De novo protein structure prediction indicated that this A28V mutation reoriented the ER retention motif located at the C-terminal of the hKir6.2, and this result may explain the trafficking defect caused by this point mutation. Our study is the first report of a novel form of late-onset PHHI that is caused by a dominant mutation in KCNJ11 and exhibits a defect in proper surface expression of Kir6.2. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|