title: Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations.
abstract: BACKGROUND
  Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism-hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.
  
  
  OBJECTIVE
  To study the genotype-phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.
  
  
  RESULTS
  Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 micromol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.
  
  
  CONCLUSIONS
  Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.
authors.affiliation: Developmental Endocrinology Research Group, Molecular Genetics Unit, London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children NHS Trust, and The Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Ritika R
authors.initials: RR
authors.lastname: Kapoor
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Piers
authors.initials: P
authors.lastname: Fulton
authors.forename: Anupam
authors.initials: A
authors.lastname: Chakrapani
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chadefaux
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.forename: Indraneel
authors.initials: I
authors.lastname: Banerjee
authors.forename: Julian P
authors.initials: JP
authors.lastname: Shield
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004827:Epilepsy / Q000503:physiopathology; D005260:Female; D005838:Genotype; D005969:Glutamate Dehydrogenase / Q000235:genetics*; D006801:Humans; D022124:Hyperammonemia / Q000201:enzymology / Q000235:genetics*; D006946:Hyperinsulinism / Q000201:enzymology / Q000235:genetics*; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins; D020125:Mutation, Missense; D010641:Phenotype; D016133:Polymerase Chain Reaction; D037761:Sirtuins / Q000235:genetics; D013577:Syndrome
chemical_list: D024101:Mitochondrial Proteins; D004247:DNA; D005969:Glutamate Dehydrogenase; C525357:SIRT4 protein, human; D037761:Sirtuins
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