Precision therapy for three Chinese families with maturity-onset diabetes of the young (MODY12).
Precision therapy for three Chinese families with maturity-onset diabetes of the young (MODY12).
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三个中国青少年发病家庭的精准治疗（MODY12）
DOI：
10.3389/fendo.2022.858096
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
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作者：
青年成熟型糖尿病（MODY）是一种罕见的单基因糖尿病。然而，MODY经常未被诊断或误诊。在本研究中，我们旨在研究糖尿病的致病基因，并为三个家族的糖尿病患者提供精准治疗。采用全外显子组测序（WES）对3个疑似MODY的家族进行种系突变筛选。候选致病变异在其他家族成员和非相关健康对照中得到验证。ABCC8基因（NM_001287174）的3个杂合错义突变，c.1555C>T (p.R519C), C 3706A>G （p.I1236V）和c.2885在A、B和C家族中分别发现了C>T （p.S962L）。所有与糖尿病共分离的突变位点都被生物信息学预测为有害的，而在非相关的健康对照中未发现。两个先证（发病年龄，8岁和12岁）对格列美脲敏感。然而，剂量不足（2毫克/天）导致酮症酸中毒。当格列美脲的剂量增加到4mg /d时，血糖仍然得到控制。一名25岁成年患者每日服用4mg格列美脲也能有效控制血糖。此外，所有患者对利拉鲁肽均敏感，利拉鲁肽能较好地控制血糖。这些数据表明ABCC8是三个糖尿病家族的致病基因。格列美脲（2mg /天）对ABCC8突变儿童血糖控制无效，而4mg /天格列美脲对成人和儿童均有效。此外，利拉鲁肽在ABCC8突变的成人和儿童中都能有效控制血糖。
Maturity-onset diabetes of the young (MODY) is rare monogenic diabetes. However, MODY is often undiagnosed or misdiagnosed. In this study, we aimed to investigate the pathogenic gene for diabetes and provide precise treatment for diabetes patients in three families. Three families with suspected MODY were enrolled and screened for germline mutations using Whole exome sequencing (WES). Candidate pathogenic variants were validated in other family members and non-related healthy controls. Three heterozygous missense mutations in the ABCC8 gene (NM_001287174), c.1555 C>T (p.R519C), c.3706 A>G (p.I1236V), and c.2885 C>T (p.S962L) were found in families A, B, and C, respectively. All mutation sites cosegregated with diabetes, were predicted to be harmful by bioinformatics and were not found in non-related healthy controls. Two probands (onset ages, 8 and 12 years) were sensitive to glimepiride. However, an insufficient dose (2 mg/day) led to ketoacidosis. When the dosage of glimepiride was increased to 4 mg/day, blood sugar remained under control. A dose of 4 mg glimepiride daily also effectively controlled blood sugar in an adult patient 25-year-old. In addition, all patients were sensitive to liraglutide, which could control blood sugar better. These data suggest that ABCC8 was the pathogenic gene in three families with diabetes. Glimepiride (2 mg/day) was not effective in controlling blood sugar in children with ABCC8 mutations, however, 4 mg/daily glimepiride was effective in both adults and children. Moreover, liraglutide was effective in controlling blood sugar in both adults and children with ABCC8 mutations.