Aims/Introduction
The adenosine triphosphate (ATP)‐sensitive potassium (KATP) channel is a key component of insulin secretion in pancreatic β‐cells. Activating mutations in ABCC8 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent NDM (PNDM).Materials and Methods
The coding regions and conserved splice sites of KCNJ11,ABCC8 and INS were screened for mutations in a 12‐year‐old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch‐clamp experiments in COS‐1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas in vitro and in the patient.Results
We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in ABCC8. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch‐clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas in vitro and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide.Conclusions
We identified the Pro1198Leu ABCC8 mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM. 相似文献Objective: To describe a family with Emberger syndrome with incomplete penetrance.
Methods: A DNA sequencing of GATA2 gene was performed in the parents and offspring (five individuals in total).
Results: The family consisted of 5 individuals with a GATA2 null mutation (c.130G>T, p.Glu44*); three of them were affected (two of which were deceased) while two remained unaffected at the age of 40 and 13 years old. The three affected siblings (two boys and one girl) presented with lymphedema of the lower limbs, recurrent warts, epistaxis and recurrent infections. Two died due to hematological abnormalities (AML and pancytopenia). In contrast, the two other family members who carry the same mutation (the mother and one brother) have not presented any symptoms and their blood tests remain normal.
Discussion: Incomplete penetrance may indicate that GATA2 haploinsufficiency is not enough to produce the phenotype of Emberger syndrome. It could be useful to perform whole exome or genome sequencing, in cases where incomplete penetrance or high variable expressivity is described, in order to probably identify specific gene interactions that drastically modify the phenotype. In addition, skewed gene expression by an epigenetic mechanism of gene regulation should also be considered. 相似文献