Liu Yanxia, Ren Shuxin, Zhu Chaofeng, Chen Sufang, Zhang Huijuan, Zhang Juan, Li Jianhua, Jiang Yanyan
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Genetic and Prenatal Diagnosis Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Acta Diabetol. 2024 Nov 18. doi: 10.1007/s00592-024-02410-1.
Although the MODY12 subtype, caused by ABCC8 mutations, is rare, it is highly sensitive to sulfonylureas. The identification of ABCC8 mutations in patients clinically diagnosed with MODY has the ability to contribute to the precise management of diabetes.
Genetic analysis of two families with MODY were conducted using whole-exome sequencing (WES) and Sanger sequencing. The spatial structures of the mutant proteins were constructed using MODELLER and PyMOL software to provide further evidence of pathogenicity.
The heterozygous missense mutations V357I and R1393H in ABCC8 were found in probands of two unrelated MODY pedigrees, which co-segregated with the hyperglycemic phenotypes in these two pedigrees. Detection of the V357I mutation enabled the proband of family A to successfully transfer from insulin to sulfonylurea (SU). After 3 months of follow-up for the SU trial, the HbA1c level of proband A improved from 12.4% at the initial diagnosis to 7.20%. Proband B was treated with insulin because of pregnancy and poor islet function. In silico analysis indicated that the R1393H mutation resulted in a longer hydrogen bond distance to L1389 and cleavage of carbon-hydrogen bonds to V1395, A1390, and L1389.
We have described two pathogenic missense mutations in ABCC8 in Chinese families with MODY. Our findings support the heterogeneity in the clinical features of MODY12 caused by ABCC8 mutations.
尽管由ABCC8突变引起的MODY12亚型较为罕见，但它对磺脲类药物高度敏感。在临床诊断为MODY的患者中鉴定ABCC8突变有助于糖尿病的精准管理。
使用全外显子组测序（WES）和桑格测序对两个MODY家族进行基因分析。使用MODELLER和PyMOL软件构建突变蛋白的空间结构，以提供致病性的进一步证据。
在两个无关的MODY家系的先证者中发现了ABCC8基因的杂合错义突变V357I和R1393H，这两个突变与这两个家系中的高血糖表型共分离。检测到V357I突变使A家族的先证者成功从胰岛素治疗转换为磺脲类药物（SU）治疗。在进行SU试验3个月的随访后，先证者A的糖化血红蛋白（HbA1c）水平从初诊时的12.4%改善至7.20%。先证者B因怀孕和胰岛功能差而接受胰岛素治疗。计算机模拟分析表明，R1393H突变导致与L1389的氢键距离延长，并导致与V1395、A1390和L1389的碳氢键断裂。
我们描述了中国MODY家系中ABCC8基因的两个致病性错义突变。我们的研究结果支持了由ABCC8突变引起的MODY12临床特征的异质性。
