Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome.
ABSTRACT The hyperinsulinism-hyperammonemia syndrome (HHS) has been shown to result from 'gain-of-function' mutations of the glutamate dehydrogenase (GlDH) gene, GLUD1. In the original report, all mutations were found in a narrow range of 27 base pairs within exons 11 and 12 which predicted an effect on the presumed allosteric domain of the enzyme and all these mutations were associated by a diminished inhibitory effect of guanosine triphosphate (GTP) on GlDH activity. We have investigated 14 patients from seven European families with mild hyperinsulinism. In four families, more than one member was affected. In eight cases hyperammonemia was documented, and eight cases had signs of significant leucine sensitivity. In one of the families, a novel heterozygous missense mutation in exon 6 [c.833C>T (R221C)] was detected, and in all other cases from six unrelated families the novel heterozygous missense mutation c.978G>A (R269H) was found in exon 7. When GIDH activity was measured in lymphocytes isolated from affected patients, both mutations were shown to result in a normal basal activity but a diminished sensitivity to GTP. It is the first time that this effect is reported for mutations located in the presumed catalytic site and outside the GTP allosteric domain of the enzyme. The observation of the high prevalence of the exon 7 mutation both in familial and sporadic cases of HHS suggests a mutation hot spot and justifies a mutation screening for this novel mutation by mismatch PCR-based restriction enzyme digestion in patients with hyperinsulinism.
- SourceAvailable from: unige.ch[Show abstract] [Hide abstract]
ABSTRACT: Glutamate is implicated in numerous metabolic and signalling functions that vary according to specific tissues. Glutamate metabolism is tightly controlled by activities of mitochondrial enzymes and transmembrane carriers, in particular glutamate dehydrogenase and mitochondrial glutamate carriers that have been identified in recent years. It is remarkable that, although glutamate-specific enzymes and transporters share similar properties in most tissues, their regulation varies greatly according to particular organs in order to achieve tissue specific functions. This is illustrated in this review when comparing glutamate handling in liver, brain, and pancreatic beta-cells. We describe the main cellular glutamate pathways and their specific functions in different tissues, ultimately contributing to the control of metabolic homeostasis at the organism level.Biochimica et Biophysica Acta 07/2008; 1777(7-8):965-72. DOI:10.1016/j.bbabio.2008.04.031 · 4.66 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Nesidioblastosis is infrequent; however, it is widely recognized as the cause of persistent infant hyperinsulinemic hypoglycemia. Among adults, insulinoma is the major cause of hyperinsulinemia hypoglycemia, but identification has also been made of cases of nesidioblastosis which are designated asnon insulinoma pancreatogena hypoglycemic syndrome´. The first case descriptions of adult nesidioblastosis were associated with other conditions such as insulinoma and neuroenodocrinal pancreatic tumors, and MEN-1. This article describes a case of nesidioblastosis concurrent with insulinoma in a 20-year old patient; the literature is reviewed; discussion is provided on possible etiology, clinical manifestation, diagnosis, treatment, and a concluding algorithm.
Conference Paper: Classification board for real time image segmentation[Show abstract] [Hide abstract]
ABSTRACT: We present the realization of a classification board, for real-time image segmentation. The classification of each pixel is completed using a real time extraction of attributes and a geometric classification method by stress polytope training, which ensures a high decision speed (100 ns per pixels) and good performance. The decision operator has been integrated in the form of a full custom circuit, and the extraction of parameters is performed using a single high density FPGAAcoustics, Speech, and Signal Processing, 1997. ICASSP-97., 1997 IEEE International Conference on; 05/1997