Molecular Genetic Characteristics And Clinical Manifestations Of MODY3 Patients

Objective:Maturity-onset diabetes of the young(MODY)is a special type of diabetes caused by familial,autosomal dominant inheritance and monogenic defect.The incidence is low,diagnosing and typing mainly rely on genetic testing.And the maturity-onset diabetes of the young type 3(MODY3)is the most common subtype,caused by the mutation of hepatic nuclear factor 1α(HNF-1α),characterized by defective β-cell insulin secretion mainly,and complicated with microvascular complications at earlier stages of the disease.Further strengthening the screening and research of the disease will not only help to achieve precise treatment of patients and evaluate the risk of disease for their family members,but also facilitate the development of clinical work and scientific research in the future.Therefore,in this research,MODY3 patients were diagnosed by HNF-1α gene detection in clinically suspected MODY patients.Moreover,the correlation between its molecular characteristics and clinical characteristics was analyzed,to identify patients at high risk of disease and reduce the rate of missed or misdiagnosis.So as to provide help for the precision treatment of MODY3 patients.Methods:Inpatients with clinical manifestations suspected to be MODY were collected in the Department of Endocrinology and Metabolism,the Fourth Affiliated Hospital of Kunming Medical University from September 2018 to December 2019.Mutation analysis of HNF-1α gene was performed by sanger sequencing to diagnose MODY3 patients.Furthermore,the mutation sites,age of onset,clinical manifestations,complications,biochemical characteristics,islet function and therapeutic differences among those were analyzed and studied.Results:1.Results of screening subjects:10 patients with clinically suspected MODY were collected.Finally,5 MODY3 patients(50%)among of them were diagnosed through the analysis of HNF-1α gene mutation.2.Mutation sites of HNF-1α gene:3 cases of p.I27L mutation,1 case of p.S487N mutation and 1 case of p.G574S mutation were discovered.The site of p.I27L mutation is located at DNA binding domain of HNF-1α gene,the site of p.S487N mutation and p.G574S mutation are located at transcriptional activation domain of HNF-1α gene.p.S487N was known missense heterozygous mutation,p.I27L and p.G574S were known homozygous mutations.3.Baseline characteristics of MODY3 patients:there were 4 males and 1 female.The onset age of 4 cases was less than 25 years old.3 cases of Han nationality,1 case of Yi nationality and 1 case of Bai nationality.Body mass index(BMI)>25kg/m2 of 3 cases.3 cases showed symptoms of "three more and one less" at the beginning of the disease.2 cases were complicated with diabetic angiopathies,and 4 case were complicated with diabetic ketoacidosis(DKA).All of them were treated with insulin to reduce blood glucose,and 3 patients were treated with insulin combined with oral antidiabetic drugs(OAD),excluding sulfonylureas.4.Biochemical characteristics of MODY3 patients:plasma glucose and plasma lipid in all cases,and homeostasis model analysis insulin resistance index(HOMA-IR)in 4 cases were elevated,compared with the normal reference ranges reported in healthy populations.And postprandial plasma glucose(PPG)was significantly higher than fasting plasma glucose(FPG)in 4 cases(>5mmol/L)in the individual’s own control.5.Islet function of MODY3 patients:steamed bread meal load test was performed in all cases.The results showed that the basal secretion of C-peptide and insulin were normal,but the secretion peak were delayed and the multiplication were poor.For specific performance,the basal secretion of C-peptide and insulin were in the normal range at 0 min in all cases.The secretion of C-peptide reached peak value at 120 min in 2 cases,did not decrease to normal at 180 min.And reached peak value at 180 min in the remaining 3 cases.The secretion of insulin reached peak value at 120 min in 3 cases,did not decrease to normal at 180 min.And reached peak value at 180 min in the remaining 2 cases.The peak value of C-peptide and insulin was less than 5 times of basal secretion(0 min)in all cases.Conclusion:1.Consistent with previous studies,the early clinical features of MODY3 patients are quite individual variation.However,most of them were characterized by impaired insulin secretion,significantly higher PPG than FPG(>5mmol/L),and easy to be complicated with microvascular complications.2.The diagnosis rate of MODY3(50%)was relatively high in this research compared to previous studies,which showed that performing genetic testing in patients who met the minimum diagnostic criteria of MODY and relaxing the genetic testing criteria(age,BMI,DKA and insulin resistance)can improve the detection rate of MODY3 to a certain extent.3.Previous studies have shown that the mutation sites of HNF-1α gene can influence the age of onset,islet function and complication rate.In this research,we found that patients with transcriptional activation domain mutations of the HNF-1αgene have a later onset age and better islet function,but are more easily to be complicated with diabetic angiopathy.