Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations.
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.
Kapoor
Ritika R
RR
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.
Flanagan
Sarah E
SE
Fulton
Piers
P
Chakrapani
Anupam
A
Chadefaux
Bernadette
B
Ben-Omran
Tawfeg
T
Banerjee
Indraneel
I
Shield
Julian P
JP
Ellard
Sian
S
Hussain
Khalid
K
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
D024101:Mitochondrial Proteins; D004247:DNA; D005969:Glutamate Dehydrogenase; C525357:SIRT4 protein, human; D037761:Sirtuins
Hum Genet. 2001 Jan;108(1):66-71
11214910
Diabetes. 2000 Apr;49(4):667-73
10871207
Mol Genet Metab. 2004 Apr;81 Suppl 1:S45-51
15050973
Arch Dis Child. 1968 Feb;43(227):69-72
5642986
J Pediatr. 2005 Mar;146(3):388-94
15756227
J Biol Chem. 1988 Sep 25;263(27):13610-4
3047128
J Biol Chem. 2007 Nov 16;282(46):33583-33592
17715127
Pediatrics. 2000 Sep;106(3):596-600
10969108
Dev Med Child Neurol. 2008 Dec;50(12):945-9
19046187
J Pediatr. 2000 Jan;136(1):69-72
10636977
Cell. 2006 Sep 8;126(5):941-54
16959573
N Engl J Med. 1998 May 7;338(19):1352-7
9571255
Pediatr Res. 2001 Sep;50(3):353-7
11518822
J Pediatr. 2001 Mar;138(3):383-9
11241047
Hum Genet. 1999 Jun;104(6):476-9
10453735
Metabolism. 1996 Aug;45(8):957-60
8769351
Seizure. 2008 Oct;17(7):658-64
18321734
Comp Biochem Physiol B. 1993 Dec;106(4):767-92
8299344
J Biol Chem. 1951 Nov;193(1):265-75
14907713
Eur J Pediatr. 2002 Jan;161(1):37-48
11808879