Lack of Glibenclamide Response in a Case of Permanent Neonatal Diabetes Caused by Incomplete Inactivation of Glucokinase

Oriola, Josep; Moreno, Francisca; Gutiérrez-Nogués, Ángel; León, Sara; García-Herrero, Carmen-María; Vincent, Olivier; Navas, María-Ángeles

doi:10.1007/8904_2014_383

Cited by 6 publications

(2 citation statements)

References 20 publications

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“…2 µm high-copy-number and integrative plasmids encoding LexA-Tsg101 were constructed by cloning the Tsg101 coding sequence in the BamH1 site of LexA(1-202)+PL 35 or a pRS402 36 derivative containing the LexA sequence under the control of the ADH1 promotor and terminator. pACT2-GK and pGBKT7-GKRP encoding GAD-GK and GBD-GKRP have been described previously 37 , as well as plasmids expressing GST-GK, GFP-GK, GKRP-Flag and GKRP-mCherry 22 . Single mutations in pACT2-GK were introduced by site-directed mutagenesis.…”

Section: Methodsmentioning

confidence: 99%

A novel reverse two-hybrid method for the identification of missense mutations that disrupt protein–protein binding

Vincent

Gutiérrez-Nogués

Trejo-Herrero

et al. 2020

Sci Rep

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The reverse two-hybrid system is a powerful method to select mutations that disrupt the interaction between two proteins and therefore to identify the residues involved in this interaction. However, the usefulness of this technique has been limited by its relative complexity when compared to the classical two-hybrid system, since an additional selection step is required to eliminate the high background of uninformative truncation mutants. We have developed a new method that combines the classical and reverse two-hybrid systems to select loss-of-binding missense mutations in a single step. The strategy used to select against truncation mutants is based on the two-hybrid interaction between a C-terminal fusion peptide and the Tsg101 protein. We have applied this method to identify mutations in human glucokinase (GK) that disrupt glucokinase regulatory protein (GKRP) binding. Our results indicate that this method is very efficient and eliminates all the truncation mutants and false positives. The mutated residues identified in GK are involved in the GKRP binding interface or in stabilizing the super-open conformation of GK that binds GKRP. This technique offers an improvement over existing methods in terms of speed, efficiency and simplicity and can be used to study any detectable protein interaction in the two-hybrid system.

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Section: Methodsmentioning

confidence: 99%

A novel reverse two-hybrid method for the identification of missense mutations that disrupt protein–protein binding

Vincent

Gutiérrez-Nogués

Trejo-Herrero

et al. 2020

Sci Rep

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“…Most frequently, heterozygous mutations in the KCNJ11 (OMIM 600937), INS (OMIM 176730) and ABCC8 (OMIM 600509) genes are associated with PNDM [ 4 ]. Despite significant progress in the elucidation of the molecular basis of PNDM during last decade, up to 40 % of patients remain with unknown etiology [ 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins

Esquiaveto-Aun

Mello

Paulino

et al. 2015

Diabetol Metab Syndr

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BackgroundPermanent neonatal diabetes mellitus (PNDM) is a rare disorder, characterized by uncontrolled hyperglycemia diagnosed during the first 6 months of life. In general, PNDM has a genetic origin and most frequently it results from heterozygous mutations in KCNJ11, INS and ABCC8 genes. Homozygous or compound heterozygous inactivating mutations in GCK gene as cause of PNDM are rare. In contrast, heterozygosis for GCK inactivating mutations is frequent and results in the maturity-onset diabetes of young (MODY), manifested by a mild fasting hyperglycemia usually detected later in life. Therefore, as an autosomal recessive disorder, GCK-PNDM should be considered in families with history of glucose intolerance or MODY in first relatives, especially when consanguinity is suspected.ResultsHere we describe two patients born from non-consanguineous parents within a family. They presented low birth weight with persistent hyperglycemia during the first month of life. Molecular analyses for KCNJ11,INS, ABCC8 did not show any mutation. GCK gene sequencing, however, revealed that both patients were compound heterozygous for two missense combined in a novel GCK-PNDM genotype. The p.Asn254His and p.Arg447Gly mutations had been inherited from their mothers and fathers, respectively, as their mothers are sisters and their fathers are brothers. Parents had been later diagnosed as having GCK-MODY.ConclusionsMutations’ in silico analysis was carried out to elucidate the role of the amino acid changes on the enzyme structure. Both p.Asn254His and p.Arg447Gly mutations appeared to be quite damaging. This is the first report of GCK-PNDM in a Brazilian family.

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Monogenic Forms of Diabetes Mellitus

Gaál

Balogh

2019

Experientia Supplementum

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Lack of Glibenclamide Response in a Case of Permanent Neonatal Diabetes Caused by Incomplete Inactivation of Glucokinase

Abstract: Hypoglycaemic drugs acting on the KATP channel might not be useful in the treatment of PNDM-GCK, even in patients carrying GCK mutations with mild kinetic defects.

Cited by 6 publications

References 20 publications

A novel reverse two-hybrid method for the identification of missense mutations that disrupt protein–protein binding

A novel reverse two-hybrid method for the identification of missense mutations that disrupt protein–protein binding

A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins

Monogenic Forms of Diabetes Mellitus

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