Linked Life Data

15579781

Source:http://linkedlifedata.com/resource/pubmed/id/15579781

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2004-12-6
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0021-972X
pubmed:author
pubmed:issnType
Print
pubmed:volume
89
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6224-34
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:15579781-ATP-Binding Cassette Transporters, pubmed-meshheading:15579781-Adenine, pubmed-meshheading:15579781-Chromosome Mapping, pubmed-meshheading:15579781-Cohort Studies, pubmed-meshheading:15579781-Electrophysiology, pubmed-meshheading:15579781-Genetic Heterogeneity, pubmed-meshheading:15579781-Guanine, pubmed-meshheading:15579781-Humans, pubmed-meshheading:15579781-Hyperinsulinism, pubmed-meshheading:15579781-Infant, Newborn, pubmed-meshheading:15579781-Islets of Langerhans, pubmed-meshheading:15579781-Mutation, pubmed-meshheading:15579781-Mutation, Missense, pubmed-meshheading:15579781-Pedigree, pubmed-meshheading:15579781-Potassium Channels, pubmed-meshheading:15579781-Potassium Channels, Inwardly Rectifying, pubmed-meshheading:15579781-Promoter Regions, Genetic, pubmed-meshheading:15579781-Receptors, Drug
pubmed:year
2004
pubmed:articleTitle
Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.
pubmed:affiliation
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't