Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase

Orphanet Journal of Rare Diseases

Khalid Hussain¹  Sian Ellard²  Sarah E Flanagan²  Enver Simsek⁴  Teoman Akcay⁶  Bernadette Chadefaux³  Simon Eaton⁵  Ritika R Kapoor⁵  Amanda J Heslegrave⁵ 

[1] Developmental Endocrinology Research Group Molecular Genetics Unit Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK;Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter EX2 5DW, Exeter, UK;Metabolic Biochemistry, Hôpital Necker–Enfants Malades, Université Paris Descartes, Paris, France;Department of Pediatrics and Division of Pediatric Endocrinology Eskisehir, Osmangazi University School of Medicine, Eskisehir, Turkey;London Centre for Paediatric Endocrinology and Metabolism, Hospital for Children NHS Trust, Great Ormond Street, London, WC1N 3JH, UK;Dept of Endocrinology, Sıslı Etfal Education and Research Hospital, Istanbul, Turkey

关键词: Leucine tolerance;    Hypoglycaemia;    Hyperinsulinism;   

Others  :  864426
DOI  :  10.1186/1750-1172-7-25

 received in 2012-01-23, accepted in 2012-05-14,  发布年份 2012

【 摘 要 】

Background

Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoA dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial β-oxidation of fatty acids. Mutations in GLUD1 encoding glutamate dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a protein-protein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with HADH mutations.

Methods

An oral leucine tolerance test was conducted in controls and nine patients with HADH mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions.

Results

Patients demonstrated severe HH (glucose range 1.7–3.2 mmol/l; insulin range 4.8-63.8 mU/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity and half maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples.

Conclusions

We conclude that GDH and HADH have a direct protein-protein interaction, which is lost in patients with HADH mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with GLUD1 mutations).

【 授权许可】

   
2012 Heslegrave et al.; licensee BioMed Central Ltd.

【 图 表 】

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