Background: Neonatal hyperinsulinaemic hypoglycaemia (HH) has recently been recognized as a consequence of mutations in HNF1A, which also cause maturity-onset diabetes of the young (MODY) later in life.
Aims: To report phenotypic and genetic investigations of two patients with functional characterisation of identified mutations in HNF1A.
Case reports: Two unrelated patients presented with HH requiring i.v. glucose administration during the neonatal period. Patient 1 repeatedly developed hyperglycemia with ketonuria during acute respiratory infections in infancy. Fasting glycaemia of 7 mmol/l was observed in patient 2 at the age of 18 months. Positive family history of diabetes was reported in both families.
Methods: DNA was analysed by directed sequencing. Thereafter, the pathogenic effect of the novel HNF1A mutations on normal HNF1A function was assessed by transcriptional activation assay in transfected HeLa cells, and DNA binding studies using in vitro expressed (TnT) proteins and analysed by electrophoretic mobility shift analysis.
Results: Two novel mutations in the HNF1A gene were detected: patient 1 carried p.Leu254Gln and patient 2 p.Asn62fs. Both mutations segregated with β-cell defect within the families. Functional investigation of the p.Leu254Gln and p.Asn62fs mutation demonstrated severely reduced transcriptional activity (~20 and ~0% activity) compared to WT HNF1A (100% activity) respectively. Both of the in vitro expressed mutant proteins failed to bind to an HNF1A site in the rat albumin promoter.
Conclusion: Complex characterisation of two patients suggests that the capacity of β-cells to respond to high demands on insulin secretion may be impaired due to mutations in HNF1A at an early age. Our clinical and functional analyses confirm the role of HNF1A in pathogenesis of HH and emphasize the importance of molecular genetic testing of the HNF1A gene in patients presented with hyperinsulinaemic hypoglycaemia.
Funding: Internal Grant Agency of Czech Ministry of Health (NT11402).
01 - 03 Oct 2015
European Society for Paediatric Endocrinology