BACKGROUND Maturity-onset diabetes of the young 3(MODY3),caused by mutations in the HNF1A gene,is the most common subtype of MODY.The diagnosis of MODY3 is critical because a low dose of sulfonylurea agents can achiev...BACKGROUND Maturity-onset diabetes of the young 3(MODY3),caused by mutations in the HNF1A gene,is the most common subtype of MODY.The diagnosis of MODY3 is critical because a low dose of sulfonylurea agents can achieve glucose control.CASE SUMMARY We describe a patient with MODY3 involving a novel splicing mutation,in whom low-dose gliclazide was sufficient to control clinically significant hyperglycemia.Sanger sequencing identified a splicing HNF1A mutation in 12q24 NM_000545.5 Intron5 c.1108-1G>A.Glycemic control has been maintained without insulin therapy for 28 mo after the diagnosis of diabetes.CONCLUSION This case report highlights a novel HNF1A gene mutation in MODY3 that is responsive to sulfonylurea therapy.展开更多
BACKGROUND Maturity-onset diabetes of the young(MODY)is the most common form of monogenic diabetes.The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year.MODY 3 is c...BACKGROUND Maturity-onset diabetes of the young(MODY)is the most common form of monogenic diabetes.The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year.MODY 3 is caused by mutation of hepatocyte nuclear factor(HNF)1A genes and is the most common MODY subtype.Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea.In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued.CASE SUMMARY A 31-year-old woman was diagnosed diabetes mellitus at 14 years old.The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance.Sanger sequencing of proband’s DNA identified mutation of HNF1A at codon 203 which changed amino acid from arginine to cysteine(R203C).This mutation was carried only by family members who have diabetes.The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide(20 mg/d).Insulin therapy was successfully discontinued.CONCLUSION We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient.Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.展开更多
Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulator...Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.展开更多
目的探讨一青少年起病的成人型糖尿病3型(maturity-onset diabetes of the young type 3,MODY3)患者家系的临床特征、分析其与肝细胞核因子1α(hepatic nuclear factor 1α,HNF1A)新位点c.47T>A变异相关性。方法绘制MODY3家系遗传图...目的探讨一青少年起病的成人型糖尿病3型(maturity-onset diabetes of the young type 3,MODY3)患者家系的临床特征、分析其与肝细胞核因子1α(hepatic nuclear factor 1α,HNF1A)新位点c.47T>A变异相关性。方法绘制MODY3家系遗传图谱,收集临床资料。通过全外显子组测序结合Sanger测序、家系共分离及生物信息学分析,鉴定HNF1A-c.47T>A变异与MODY3的关联性。结果家系7例MODY3患者均携带HNF1A-c.47T>A杂合变异;AlphaFold2预测该变异导致二聚体结构域首对α螺旋构象改变。结论综合家系共分离分析、同源序列保守性分析、蛋白结构预测等分析方法,按照美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)指南分类,判定HNF1A-c.47T>A为MODY3的致病性变异;本研究报道了这一新型致病性变异,扩展了MODY3的变异谱,通过揭示其对蛋白质二聚体结构的破坏,为携带此类变异的患者诊疗提供了潜在分子机制依据。展开更多
由肝细胞核因子1A(HNF1A)基因突变引起的青少年起病的成年型糖尿病(maturity-onset diabetes of the young,MODY)简称为HNF1A-MODY,约占所有类型糖尿病的1%~3%。由于其临床表现异质性高,与1型、2型糖尿病临床特征存在交叉重叠,易漏诊或...由肝细胞核因子1A(HNF1A)基因突变引起的青少年起病的成年型糖尿病(maturity-onset diabetes of the young,MODY)简称为HNF1A-MODY,约占所有类型糖尿病的1%~3%。由于其临床表现异质性高,与1型、2型糖尿病临床特征存在交叉重叠,易漏诊或误诊为1型糖尿病(type 1 diabetes mellitus,T1DM)以及2型糖尿病(type 2 diabetes mellitus,T2DM)。因此,尽早诊断有助于为患者提供安全有效的治疗方案,改善长期预后,提高生存质量,降低医疗成本。文章结合国内外研究进展,对HNF1A-MODY的流行病学、临床特征、诊断及治疗策略进行综述,旨在为HNF1A-MODY的诊断提供依据,有望对其个体化治疗提供帮助。展开更多
基金Supported by National Natural Science Foundation of China,No.81870593 and No.82170865Quality Improvement of Postgraduate Education in Shandong Province,No.SDYAL19156.
文摘BACKGROUND Maturity-onset diabetes of the young 3(MODY3),caused by mutations in the HNF1A gene,is the most common subtype of MODY.The diagnosis of MODY3 is critical because a low dose of sulfonylurea agents can achieve glucose control.CASE SUMMARY We describe a patient with MODY3 involving a novel splicing mutation,in whom low-dose gliclazide was sufficient to control clinically significant hyperglycemia.Sanger sequencing identified a splicing HNF1A mutation in 12q24 NM_000545.5 Intron5 c.1108-1G>A.Glycemic control has been maintained without insulin therapy for 28 mo after the diagnosis of diabetes.CONCLUSION This case report highlights a novel HNF1A gene mutation in MODY3 that is responsive to sulfonylurea therapy.
基金Supported by Mahidol University Research Grant,Nos.R015810001and 016120003(to Nattachet Plengvidhya)Siriraj Research Grant for Research and Development,Faculty of Medicine Siriraj Hospital,Mahidol University,No.R015934015(to Tassanee Narkdontri and Watip Tangjittipokin)Thailand Research Fund grants,Nos.TRG5780113(to Watip Tangjittipokin),BRG5280008(to Nattachet Plengvidhya),and IRG5980006(to Pa-thai Yenchitsomanus)
文摘BACKGROUND Maturity-onset diabetes of the young(MODY)is the most common form of monogenic diabetes.The disease is transmitted in autosomal dominant mode and diabetes is usually diagnosed before age 25 year.MODY 3 is caused by mutation of hepatocyte nuclear factor(HNF)1A genes and is the most common MODY subtype.Diagnosis of MODY 3 is crucial since glycemic control can be accomplished by very low dose of sulfonylurea.In this report we described a Thai MODY 3 patient who had excellence plasma glucose control by treating with glicazide 20 mg per day and insulin therapy can be discontinued.CASE SUMMARY A 31-year-old woman was diagnosed diabetes mellitus at 14 years old.The disease was transmitted from her grandmother and mother compatible with autosomal dominant inheritance.Sanger sequencing of proband’s DNA identified mutation of HNF1A at codon 203 which changed amino acid from arginine to cysteine(R203C).This mutation was carried only by family members who have diabetes.The patient has been treated effectively with a combination of oral hypoglycemic agents and must include a very low dose of glicazide(20 mg/d).Insulin therapy was successfully discontinued.CONCLUSION We demonstrated a first case of pharmacogenetics in Thai MODY 3 patient.Our findings underscore the essential role of molecular genetics in diagnosis and guidance of appropriate treatment of diabetes mellitus in particular patient.
基金the European Structural and Investment Funded Grant"Cardio Metabolic"(#KK.01.2.1.02.0321)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010)+2 种基金the European Regional Development Fund Grant,project"CRISPR/Cas9-CasMouse"(#KK.01.1.1.04.0085)the European Structural and Investment Funded Project of Centre of Competence in Molecular Diagnostics(#KK.01.2.2.03.0006)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010).
文摘Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
文摘目的探讨一青少年起病的成人型糖尿病3型(maturity-onset diabetes of the young type 3,MODY3)患者家系的临床特征、分析其与肝细胞核因子1α(hepatic nuclear factor 1α,HNF1A)新位点c.47T>A变异相关性。方法绘制MODY3家系遗传图谱,收集临床资料。通过全外显子组测序结合Sanger测序、家系共分离及生物信息学分析,鉴定HNF1A-c.47T>A变异与MODY3的关联性。结果家系7例MODY3患者均携带HNF1A-c.47T>A杂合变异;AlphaFold2预测该变异导致二聚体结构域首对α螺旋构象改变。结论综合家系共分离分析、同源序列保守性分析、蛋白结构预测等分析方法,按照美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)指南分类,判定HNF1A-c.47T>A为MODY3的致病性变异;本研究报道了这一新型致病性变异,扩展了MODY3的变异谱,通过揭示其对蛋白质二聚体结构的破坏,为携带此类变异的患者诊疗提供了潜在分子机制依据。
