Muscle Dysfunction Caused by a K _ATP Channel Mutation in Neonatal Diabetes Is Neuronal in Origin

Abstract

Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) and balance problems. The diabetes arises from suppressed insulin secretion by overactive KATP channels in pancreatic beta-cells, but the source of the motor phenotype is unknown. By using mice carrying a human Kir6.2 mutation (Val59-->Met59) targeted to either muscle or nerve, we show that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. We also identify locomotor hyperactivity as a feature of KATP channel overactivity. These findings suggest that drugs targeted against neuronal, rather than muscle, KATP channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability.

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

“…Thus, the muscle disorders in patients with KCNJ11 mutations do not seem ascribable to changes in muscle membrane excitability. Furthermore, they are ascribable to the effects of the mutation in central nervous system cells rather than to muscle excitability impairments (33). None of our patients had a history of recurrent severe hypoglycemia.…”

Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes

“…These range from severe developmental delay and epilepsy diagnosed before 1 year (DEND syndrome) to a milder phenotype known as intermediate DEND syndrome (iDEND) (10). The neurological features are consistent with the expression of mutated K ATP channels in neurons (11). In a minority of cases, the neurological features may be incidental or secondary to complications of diabetes such as ketoacidosis and severe hypoglycaemia (12).…”

Current understanding of KATP channels in neonatal diseases: focus on insulin secretion disorders

“…Also, muscle weakness and ataxic gait in a patient with a Kir6.2 mutation was improved by treatment with gliclazide, which interacts only with SUR1 [174] . More definitive evidence comes from a recent study by Clark et al, in which hemizygous mice that selectively express the V59M Kir6.2 mutation in muscle or neurons were examined [172] . Behaviourally, transgenic mice with the neuronal V59M Kir6.2 mutation display the same motor impairments as seen in human DEND.…”

“…Neurons, like pancreatic beta-cells, mostly contain www.chinaphar.com Quan Y et al Acta Pharmacologica Sinica npg K ATP channels made up of Kir6.2 and SUR1 subunits, whereas muscle K ATP channels are composed of Kir6.2 and SUR2A subunits. In fact, it has been shown that the Kir6.2 V59M mutation specifically enhances the flow of current through K ATP channels composed of Kir6.2/SUR1 subunits, but has no effect on Kir6.2/SUR2A K ATP channels [172] . Thus, the V59M mutation selectively targets the pancreas and neurons while sparing the muscle.…”

“…There are fifteen Kir6.2 mutations and two SUR1 mutations that may cause DEND and iDEND [149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168] . In particular, the V59M mutation in Kir6.2 is the most common cause of iDEND [44,142,168,172] . The genetic basis of DEND suggests that mutation of this channel is responsible for all of the observed symptoms, and this notion is strengthened by the fact that K ATP channel subunits are expressed in the affected tissues, namely the brain, muscle and pancreas.…”