title: KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.
abstract: Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.
authors.affiliation: Laboratory of Molecular Endocrinology and Metabolism, the Diabetes Unit, and the Scientific Directorate, Bambino Gesù Pediatric Hospital, Scientific Institute (IRCCS), Rome, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Massa
authors.forename: Dario
authors.initials: D
authors.lastname: Iafusco
authors.forename: Elena
authors.initials: E
authors.lastname: D'Amato
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Bruno
authors.initials: B
authors.lastname: Pasquino
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tonini
authors.forename: Francesco
authors.initials: F
authors.lastname: Dammacco
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zanette
authors.forename: Franco
authors.initials: F
authors.lastname: Meschi
authors.forename: Ottavia
authors.initials: O
authors.lastname: Porzio
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Bottazzo
authors.forename: Antonino
authors.initials: A
authors.lastname: Crinó
authors.forename: Renata
authors.initials: R
authors.lastname: Lorini
authors.forename: Franco
authors.initials: F
authors.lastname: Cerutti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vanelli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Barbetti
mesh_terms: D004252:DNA Mutational Analysis; D003920:Diabetes Mellitus / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D000099161:Kcnj11 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel