Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome

2001 ◽  
Vol 108 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Ren� Santer ◽  
Martina Kinner ◽  
Andrea Superti-Furga ◽  
Reinhard Schneppenheim ◽  
Ertan Mayatepek ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Congenital Hyperinsulinism ◽  
Missense Mutations

Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome

2000 ◽  
Vol 136 (1) ◽  
pp. 69-72 ◽  
Author(s):  
Yuko Miki ◽  
Tomohiko Taki ◽  
Toshihiro Ohura ◽  
Hitoshi Kato ◽  
Masayoshi Yanagisawa ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Congenital Hyperinsulinism ◽  
Missense Mutations ◽  
Dehydrogenase Gene

scholarly journals Clinical and Molecular Spectrum of Glutamate Dehydrogenase Gene Defects in 26 Chinese Congenital Hyperinsulinemia Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Chang Su ◽  
Xue-Jun Liang ◽  
Wen-Jing Li ◽  
Di Wu ◽  
Min Liu ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
De Novo ◽  
Mutational Analysis ◽  
Age At Onset ◽  
Normal Serum ◽  
Protein Restriction ◽  
Chinese Patients ◽  
Congenital Hyperinsulinism ◽  
Missense Mutations ◽  
De Novo Mutations

Objective. To characterize the genotype and phenotype of Chinese patients with congenital hyperinsulinism (CHI) caused by activating mutations in GLUD1, the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH). Methods. The clinical data of glutamate dehydrogenase hyperinsulinism (GDH-HI) patients were reviewed, and gene mutations were confirmed by whole exome sequencing (WES) and Sanger DNA sequencing. Results. Twenty-six patients with GDH-HI heterozygous missense mutations were identified from 240 patients diagnosed as congenital hyperinsulinism over past 15 years. The median age at onset was 8 months (range: 1 day of life to 3 years). Seizure disorder was common in our cohort of patients (23/26). Four patients had normal serum ammonia levels; the median serum concentration was 101 μmol/L (range: 37–190 μmol/L). Hypoglycemic symptoms could be triggered by fasting or protein meals in all patients while blood glucose could be well controlled in all patients with diazoxide. Dosage of diazoxide could be reduced by protein restriction. Attempts to lower ammonia levels failed with different therapies such as protein restriction, benzoate, or N-carbamoyl glutamate. In follow-up, 15 of 26 patients had normal intelligence. Eleven patients developed epilepsy at the age of 6 months to 11 years. De novo mutations in GLUD1 were found in 24 cases, and dominant inheritance was observed in the other two; all were heterozygous. A total of 35% (9/26) patients carried c.1493C>T (p.S445L) mutation. Conclusions. Phenotypic heterogeneity of GDH-HI patients was observed within the Chinese cohort in the present study. The fact that most patients had a GLUD1 p. S445L mutation implies that this site could be a hotspot in Chinese patients. A high frequency of GDH-HI with normal ammonia has been reported in this study. Hence, GLUD1 mutational analysis may be an important method to differential diagnosis of GDH-HI from other diazoxide-responsive CHI in Chinese patients.

PNC2 (SLC25A36) deficiency associated with the hyperinsulinism/hyperammonemia syndrome

2021 ◽  
Author(s):  
Maher A Shahrour ◽  
Francesco Massimo Lasorsa ◽  
Vito Porcelli ◽  
Imad Dweikat ◽  
Maria Antonietta Di Noia ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Hela Cells ◽  
Nucleotide Metabolism ◽  
Congenital Hyperinsulinism ◽  
Inner Mitochondrial Membrane ◽  
Pathogenic Variants ◽  
Pyrimidine Nucleotide ◽  
Biochemical Assays ◽  
Whole Exome ◽  
Repeat Domain

Abstract Context The hyperinsulinism/hyperammonemia (HI/HA) syndrome, the second most common form of congenital hyperinsulinism, has been associated to dominant mutations in GLUD1, coding for the mitochondrial enzyme glutamate dehydrogenase, that increase enzyme activity by reducing its sensitivity to allosteric inhibition by GTP. Objective To identify the underlying genetic aetiology in two siblings who presented with the biochemical features of HI/HA syndrome but did not carry pathogenic variants in GLUD1, and to determine the functional impact of the newly identified mutation. Main Outcome Measures The patients were investigated by whole exome sequencing. Yeast complementation studies and biochemical assays on the recombinant mutated protein were performed. The consequences of stable slc25a36 silencing in HeLa cells were also investigated. Results A homozygous splice site variant was identified in solute carrier family 25, member 36 (SLC25A36), encoding the pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine as well as guanine nucleotides across the inner mitochondrial membrane. The mutation leads to a 26 aa in-frame deletion in the first repeat domain of the protein which abolished transport activity. Furthermore, knockdown of slc25a36 expression in HeLa cells caused a marked reduction in the mitochondrial GTP content which likely leads to an hyperactivation of glutamate dehydrogenase in our patients. Conclusions We report for the first time a mutation in PNC2/SLC25A36 leading to HI/HA and provide functional evidence of the molecular mechanism responsible for this phenotype. Our findings underscore the importance of mitochondrial nucleotide metabolism and expand the role of mitochondrial transporters in insulin secretion.

A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA)

2016 ◽  
Vol 29 (3) ◽  
Author(s):  
Chen Fang ◽  
Xin Ding ◽  
Yun Huang ◽  
Jian Huang ◽  
Pengjun Zhao ◽  
...  
Keyword(s):  
Birth Weight ◽  
Missense Mutation ◽  
Glutamate Dehydrogenase ◽  
De Novo ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Congenital Hyperinsulinism ◽  
Normal Birth Weight ◽  
Normal Birth

AbstractHyperinsulinism-hyperammonemia (HI/HA) syndrome, often characterized by recurrent symptomatic hypoglycemia and persistent hyperammonemia, is the second most frequent cause of the congenital hyperinsulinism (CHI). Here, we reported a patient with normal birth weight, repeated seizures, untreatable hypoglycemia, and persistent, mild hyperammonemia. The genetic diagnosis revealed that the patient carried a heterozygous, de novo missense mutation (N410I, c.1401A>T) in the glutamate dehydrogenase 1 gene (

scholarly journals A Japanese Case of Congenital Hyperinsulinism with Hyperammonemia Due to a Mutation in Glutamate Dehydrogenase (GLUD1) Gene.

2001 ◽  
Vol 40 (1) ◽  
pp. 32-37 ◽  
Author(s):  
Kazuki YASUDA ◽  
Naoya KODA ◽  
Hiroko KADOWAKI ◽  
Yoshihiro OGAWA ◽  
Satoshi KIMURA ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Congenital Hyperinsulinism ◽  
Japanese Case
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