Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
Hyperinsulinism of infancy is a genetically heterogeneous disease characterized by dysregulation of insulin secretion resulting in severe hypoglycemia. To date, mutations in five different genes, the sulfonylurea receptor (SUR1, ABCC8), the inward rectifying potassium channel (K(IR)6.2, KCNJ11), glucokinase (GCK), glutamate dehydrogenase (GLUD1), and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), have been implicated. Previous reports suggest that, in 40% of patients, no mutation can be identified in any of these genes, suggesting additional locus heterogeneity. However, previous studies did not screen all five genes using direct sequencing, the most sensitive technique available for mutation detection. We selected 15 hyperinsulinism of infancy patients and systematically sequenced the promoter and all coding exons and intron/exon boundaries of ABCC8 and KCNJ11. If no mutation was identified, the coding sequence and intron/exon boundaries of GCK, GLUD1, and SCHAD were sequenced. Seven novel mutations were found in the ABCC8 coding region, one mutation was found in the KCNJ11 coding region, and one novel mutation was found in each of the two promoter regions screened. Functional studies on beta-cells from six patients showed abnormal ATP-sensitive K+ channel function in five of the patients; the sixth had normal channel activity, and no mutations were found. Photolabeling studies using a reconstituted system showed that all missense mutations altered intracellular trafficking. Each of the promoter mutations decreased expression of a reporter gene by about 60% in a heterologous expression system. In four patients (27%), no mutations were identified. Thus, further genetic heterogeneity is suggested in this disorder. These patients represent a cohort that can be used for searching for mutations in other candidate genes.
Tornovsky
Sharona
S
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Crane
Ana
A
Cosgrove
Karen E
KE
Hussain
Khalid
K
Lavie
Judith
J
Heyman
Ma'ayan
M
Nesher
Yaron
Y
Kuchinski
Na'ama
N
Ben-Shushan
Etti
E
Shatz
Olga
O
Nahari
Efrat
E
Potikha
Tamara
T
Zangen
David
D
Tenenbaum-Rakover
Yardena
Y
de Vries
Liat
L
Argente
Jesús
J
Gracia
Ricardo
R
Landau
Heddy
H
Eliakim
Alon
A
Lindley
Keith
K
Dunne
Mark J
MJ
Aguilar-Bryan
Lydia
L
Glaser
Benjamin
B
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000225:Adenine; D002874:Chromosome Mapping; D015331:Cohort Studies; D004594:Electrophysiology; D018740:Genetic Heterogeneity; D006147:Guanine; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000503:physiopathology; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000503:physiopathology; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000225:Adenine; D006147:Guanine; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human