Rozenkova Klara, Nessa Azizun, Obermannova Barbora, Elblova Lenka, Dusatkova Petra, Sumnik Zdenek, Lebl Jan, Hussain Khalid, Pruhova Stepanka
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J Pediatr Endocrinol Metab. 2017 Nov 27;30(12):1311-1315. doi: 10.1515/jpem-2017-0163.
Congenital hyperinsulinism (CHI) is frequently caused by mutations in one of the KATP channel subunits encoded by the genes ABCC8 and KCNJ11. The effect of simultaneous mutations in both of these genes on the pancreatic β-cell function is not known and patients with CHI carrying both ABCC8 and KCNJ11 mutations have not yet been reported. We questioned if a combination of heterozygous mutations in the ABCC8 and KCNJ11 genes could also lead to β-cell dysfunction presenting as CHI.
As a model, we used a patient with transient CHI that paternally inherited novel heterozygous mutations in ABCC8 (p.Tyr1293Asp) and KCNJ11 (p.Arg50Trp) genes. The pathogenic effects on the pancreatic β-cells function were examined in an in vitro functional study using radioactive rubidium efflux assay.
We showed that the activation of the mutated KATP channels by diazoxide was decreased by 60.9% in the channels with the heterozygous combination of both mutations compared to the wild type channels. This could indicate the pathogenic effect on the pancreatic β-cell function leading to CHI although conclusive evidence is needed to be added.
Our findings may widen the spectrum of genetic causes of CHI and suggest a novel pathogenic mechanism of CHI that must however, be further investigated.
先天性高胰岛素血症（CHI）常由ABCC8和KCNJ11基因编码的KATP通道亚基之一发生突变引起。这两个基因同时发生突变对胰腺β细胞功能的影响尚不清楚，且尚未有携带ABCC8和KCNJ11双突变的CHI患者的报道。我们质疑ABCC8和KCNJ11基因的杂合突变组合是否也会导致表现为CHI的β细胞功能障碍。
作为模型，我们使用了一名患有短暂性CHI的患者，其从父亲那里遗传了ABCC8（p.Tyr1293Asp）和KCNJ11（p.Arg50Trp）基因的新型杂合突变。使用放射性铷外流试验在体外功能研究中检测对胰腺β细胞功能的致病作用。
我们发现，与野生型通道相比，两种突变杂合组合的通道中，二氮嗪对突变型KATP通道的激活作用降低了60.9%。这可能表明对胰腺β细胞功能有致病作用，导致CHI，不过还需要补充确凿的证据。
我们的发现可能会拓宽CHI的遗传病因谱，并提示一种CHI的新型致病机制，然而，这一机制仍需进一步研究。
