Background: Hyperinsulinaemic hypoglycaemia (HH) can be transient or permanent. Transient HH (spontaneous resolution of HH within few weeks) is associated with intrauterine growth restriction, maternal diabetes, erythroblastosis fetalis etc. Transient HH has not been reported with ABCC8/KCNJ11 mutations, which are the commonest cause of HH.
Aim: Molecular characterisation of a novel ABCC8 mutation associated with a transient HH phenotype seen in a family with two affected cousins.
Patients and methods: Two cousins developed transient HH in the neonatal period, which lasted 812 weeks. Molecular genetic analysis identified a novel maternally inherited heterozygous ABCC8 mutation (c.4547C>T; p.T1516M). Point mutation was introduced in the hamster SUR1 cDNA in the pcDNA3.1 plasmid by site-directed mutagenesis. HEK293 cells were transfected with mutant hamster SUR1 cDNA and WT human Kir6.2 cDNA using FuGENE. Functional properties of reconstituted KATP channels were studied using whole-cell patch-clamp recordings. Both homogenous and heterozygous expressions of the mutants were studied.
Results: Negligible KATP currents (current equivalent to endogenous HEK293 current) were noticed when p.T1516M SUR1 subunit was expressed with WT Kir6.2 subunit (44±13pA/pF vs. 48±13pA/pF; P=ns). This clearly established the pathogenicity of T1516M mutation, which is located in the nucleotide-binding domain 2 (NBD2) region of SUR1. With heterozygous expression as seen in the proband, KATP currents equivalent to WT KATP currents were observed (325±54pA/pF vs. 229±56pA/pF; P=ns). The WT SUR1 subunit was able to rescue the function of the mutant SUR1 subunit.
Conclusion: This study extends the clinical phenotypes reported with ABCC8 mutations to transient HH. Molecular characterisation was consistent with the observed clinical phenotype.
Funding information: The work was supported by MRC UK.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology