Department of Pediatrics, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Pediatrics, Shandong Provincial Lanling People's Hospital, Linyi, China.
Pediatr Diabetes. 2022 Aug;23(5):588-596. doi: 10.1111/pedi.13388. Epub 2022 Jul 8.
To confirm the diagnosis of a 13-year-old adolescent with familial diabetes and further examine his genetic pathogeny.
Clinical data were collected, and genetic examination was performed. PolyPhen-2 and Mutation Taster were used to predict the deleterious effects of the variant. Clustal Omega software was used to confirm the conservation of amino acid substitutions. To examine changes in the expression of proteins, recombinant vectors were constructed, and the expression of wild-type and variant target genes was detected through quantitative polymerase chain reaction. Furthermore, the wild-type and variant eukaryotic recombinant vectors were treated with a ubiquitin degradation inhibitor (MG132) and a lysosomal degradation pathway inhibitor (CQ, 3-mA). The expression of target proteins was detected through Western blot analysis.
The patient had hyperglycaemia (27 mmol/L), a high HbA1c level (13.1%), a decreased C-peptide level (0.63 ng/ml) and no diabetes antibodies. The patient had a family history of diabetes. The novel variation of ABCC8 c.2477G>A was detected in the proband and his relatives. The mutation was predicted to be harmful. Changes in the protein structure were observed. The ABCC8 c.2477G >A variant resulted in an increase in ABCC8 expression. Furthermore, changes in the expression of the ABCC8 variant was observed after 3-MA treatment, especially after treatment with MG132. At the follow-up, the patient's glucose level was normal without drug therapy for more than 2 years until until he started taking Trelagliptin Succinate to control hyperglycemia within the recent 6 months.
The diagnosis of maturity-onset diabetes of the young (MODY)12 was confirmed in our patient. The ABCC8 variant inhibited both ubiquitination and autophagy lysosome degradation pathways, especially the ubiquitination degradation pathway.
确诊一名 13 岁青少年的家族性糖尿病，并进一步研究其遗传病因。
收集临床资料并进行基因检测。使用 PolyPhen-2 和 Mutation Taster 预测变异的有害影响。使用 Clustal Omega 软件确认氨基酸替换的保守性。构建重组载体，检测野生型和变异型目的基因的表达，通过定量聚合酶链反应。此外，用泛素降解抑制剂（MG132）和溶酶体降解途径抑制剂（CQ，3-mA）处理野生型和变异型真核重组载体。通过 Western blot 分析检测目的蛋白的表达。
患者出现高血糖（27mmol/L）、高 HbA1c 水平（13.1%）、低 C 肽水平（0.63ng/ml）和无糖尿病抗体。患者有糖尿病家族史。在先证者及其亲属中发现了 ABCC8 c.2477G>A 的新变异。该突变被预测为有害。观察到蛋白质结构的变化。ABCC8 c.2477G >A 变异导致 ABCC8 表达增加。此外，在 3-MA 处理后观察到 ABCC8 变异的表达变化，尤其是在用 MG132 处理后。在随访中，患者的血糖水平正常，未经药物治疗超过 2 年，直到最近 6 个月开始服用替格列汀琥珀酸盐控制高血糖。
我们的患者被确诊为青少年发病的成年型糖尿病（MODY）12。ABCC8 变异抑制了泛素化和自噬溶酶体降解途径，尤其是泛素化降解途径。
