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
Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem;there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode...Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem;there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode of inheritance. This type is nominates Maturity onset diabetes of the young (MODY). The prevalence of MODY is difficult to access, and patients with MODY genes mutations are often identified during routine screening for other purposes. MODY2 was linked to glucokinase gene (GCK) mutations, and accounted for 8% to 56% of MODY, with the highest prevalence found in the southern Europe. The aim of this study was to examine the prevalence and nature of mutations in GCK gene in Iranian paients. We have screened GCK mutations by polymerase chain reaction (PCR);single stranded conformation polymorphism (SSCP) technique in 12 Iranian families with clinical diagnosis of MODY, included 30 patients (8 males and 22 females) and their 21 family members. PCR products with abnormal mobility in denaturing gradient gel electrophoresis (DGGE) were directly sequenced. We identified 6 novel mutations in GCK gene in Iranian families (corresponding to 36.6% prevalence). Our findings and the last study on MODY1 highlight that in addition to GCK, other MODY genes such as MODY3 and MODYX may play a significant role in diabetes characterized by monogenic autosomal dominant transmission. There is an important point that the genetic recognation can be used to pre-symptomatically identify family members at risk for developing MODY.展开更多
Positive diagnosis of diabetes is currently easy, but typing diagnosis of diabetes still remains a challenge for every clinician. It is currently accepted that types of diabetes apart from T1D and T2D can expand and i...Positive diagnosis of diabetes is currently easy, but typing diagnosis of diabetes still remains a challenge for every clinician. It is currently accepted that types of diabetes apart from T1D and T2D can expand and include several forms of diabetes mellitus;From gestational diabetes, to all forms of secondary diabetes mellitus due to medications, intercurrent disease but also infections, and finally monogenic diabetes, whose diagnosis is not always easy to establish. The aim is to reveal the difficulties that clinicians may face in the process of etiological diagnosis regarding the suspicion of this type of monogenic diabetes, through the study of 2 cases, in which MODY type diabetes was suspected. Today we recognize 17 different genetic mutations that can all lead to MODY diabetes, the most common mutation of which is GCK coding for the glucokinase, the real sensor of pancreatic Beta-cell. The truly stable glycemic profile, with an A1C ranging between 7% and 7.5%, confirmed with a TIR always above 70% and a good MAGE, but also the rarity of degenerative complications and pharmacological therapeutic abstention which can last for years, these would be the most striking clinical characteristics of a GCK MODY.展开更多
报告1例青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)3型(MODY3)合并5型(MODY5)患者的临床特征、诊断及治疗,并复习相关文献。利用MODY(1~14型)基因外显子二代测序和Sanger测序验证MODY患者及其母亲,结合临床...报告1例青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)3型(MODY3)合并5型(MODY5)患者的临床特征、诊断及治疗,并复习相关文献。利用MODY(1~14型)基因外显子二代测序和Sanger测序验证MODY患者及其母亲,结合临床表型及基因检测结果,该患者诊断为MODY3合并MODY5,给予胰岛素及利格列汀治疗,观察血糖变化。临床医师应提高对MODY临床表型的认识,对于合并先天性胰腺和肾脏发育不全、高密度脂蛋白胆固醇升高,无自发酮症、胰岛素分泌缺陷,胰岛自身抗体阴性,无明显胰岛素抵抗,非肥胖的青少年糖尿病患者应行基因检测以筛查MODY,精准诊断并予以个体化治疗将有助于血糖水平达标及改善生活质量,并指导优化生育。展开更多
肝细胞核因子1α(HNF1α)不仅是调节葡萄糖代谢的重要转录因子,还参与肝、胰等多个器官中蛋白质合成、物质代谢、增殖分化相关基因的表达调控。HNF1α突变或表达异常引发包括青少年糖尿病3型(maturity onset diabetes of young 3,MODY3...肝细胞核因子1α(HNF1α)不仅是调节葡萄糖代谢的重要转录因子,还参与肝、胰等多个器官中蛋白质合成、物质代谢、增殖分化相关基因的表达调控。HNF1α突变或表达异常引发包括青少年糖尿病3型(maturity onset diabetes of young 3,MODY3)在内的多种代谢疾病。Ser249是HNF1α重要的功能位点,该位点受ATM蛋白激酶直接磷酸化修饰,并可能是ATM蛋白激酶影响葡萄糖代谢的效应靶点,也可能是共济失调毛细血管扩张症(ataxia telangiectasia,AT)患者糖代谢异常的致病靶点。为进一步研究Ser249磷酸化在体内的功能,本文构建人源野生型HNF1α转基因小鼠(WT小鼠)和HNF1αS249A转基因小鼠(S249A小鼠),对其基础代谢水平和葡萄糖代谢能力进行检测。相较于对照小鼠,S249A小鼠的多项基础代谢指标异常,WT小鼠未显示差异;但当小鼠接受刺激后,无论是注射葡萄糖,还是丙酮酸或胰岛素,相较于各自的对照小鼠,WT小鼠都表现出更强的反应性,而S249A小鼠的糖异生反应和胰岛素敏感性均未显示出差异。实时定量PCR结果表明,WT小鼠肝的多个糖代谢基因表达上调,但S249A小鼠肝中糖代谢基因上调幅度明显小于WT小鼠。本研究提示,HNF1αSer249突变导致小鼠糖代谢异常,可能与磷酸化修饰失调进而影响其转录活性有关。展开更多
The disorder, Maturity Onset of Diabetes of the young (MODY) is a monogenic form of Non-Insulin dependent Diabetes Mellitus (NIDDM), characterized by autosomal dominant mode of inheritance and onset is usually before ...The disorder, Maturity Onset of Diabetes of the young (MODY) is a monogenic form of Non-Insulin dependent Diabetes Mellitus (NIDDM), characterized by autosomal dominant mode of inheritance and onset is usually before 25 years of age. Clinical studies of subjects with the different forms of MODY indicate that each is associated with a different defect in the normal pattern of glucose stimulated insulin secretion. MODY can result from mutations in any one of the six different genes, one of which encodes the glycolytic enzyme Glucokinase, associated with MO-DY2 and the other five encode transcription factors HNF4-alpha associated with MODY 1, HNF1-alpha associated with MODY 3, IPF with MODY 4, HNF1-Beta with MODY 5 and NeuroD1 with MO-DY6. Studies related to mutations in the MODY genes have led to a better understanding of the genetic causes of the Beta cell dysfunction as genetic factors plays a great role in this disorder. Objective: To investigate the mutation pattern in the different transcription factor genes with special reference to HNF1-alpha which are highly penetrant with 63% mutation carriers manifesting clinical diabetes by the age of 25 years. Hence study of mutation pattern in this gene is essential in our population i.e. Eastern Indian population. Our study is focused on HNF1-alpha related to MODY 3, which is the most common one. Methods: In our study enzyme amplification (PCR) of the 10 target exons of the said gene with simultaneous mutation detection in them by PCR-SSCP (Polymerase chain reaction-single strand conformational polymorphism) reaction analysis method was attempted by screening of exon 1 - 10 with respect to normal healthy controls without Diabetes Mellitus. The nature of the specific mutations was also determined by sequencing. Result: It was observed that maximum number of variations exist in exon 5 of HNF1-alpha gene which may be referred to as “Mutational Hotspot” in our Eastern Indian population. Conclusions: Since maximum number of variations exists in exon 5 of the said gene, hence one can initially go for exon5 followed by other exons, while screening for pathogenic MODY 3 mutations in the responsible gene by PCR-SSCP method.展开更多
目的报道1例中国人葡萄糖激酶(glucokinase,GCK)新发基因突变导致青少年起病的成人型糖尿病2型(maturity-onset diabetes of the young,type 2,MODY2)家系,分析其遗传学特征及临床特点。方法对1例MODY2家系行基因测序、临床资料采集及...目的报道1例中国人葡萄糖激酶(glucokinase,GCK)新发基因突变导致青少年起病的成人型糖尿病2型(maturity-onset diabetes of the young,type 2,MODY2)家系,分析其遗传学特征及临床特点。方法对1例MODY2家系行基因测序、临床资料采集及分析。结果调查此家系成员共18人,其中先证者及其弟、父亲、叔父、堂弟等父系成员11人罹患糖尿病;先证者及其弟、父亲、叔父均存在GCK基因杂合同义突变(exon1:c.45G>A:p.K15K),生物信息学功能预测提示该突变可能影响mRNA剪接而致GCK功能受损,国内研究人群尚未见此突变报道;先证者及其弟糖化血红蛋白分别为6.49%、6.72%,空腹血糖分别为6.80、7.01 mmol/L,糖尿病自身抗体谱均为阴性,6~18个月随访示血糖水平保持稳定。结论此MODY2家系中GCK基因杂合同义突变(exon1:c.45G>A:p.K15K)为中国人新发突变位点,其临床表现为轻度、持续稳定的空腹高血糖及糖化血红蛋白升高,不应低估GCK基因同义突变的致病性。展开更多
Background Mutations in the hepatocyte nuclear factor-lA gene cause the type 3 form of maturity-onset diabetes of the young （MODY3）. This study was undertaken to determine mutations and sequence variations of the HN...Background Mutations in the hepatocyte nuclear factor-lA gene cause the type 3 form of maturity-onset diabetes of the young （MODY3）. This study was undertaken to determine mutations and sequence variations of the HNF-1A gene in Chinese with familial early-onset and/or multiplex diabetes mellitus.展开更多
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.
文摘Non insulin dependent diabetes mellitus (NIDDM) as a most common form of diabetes is a major public health problem;there is a subgroup of NIDDM patients who develop the disease at an early age and show a dominant mode of inheritance. This type is nominates Maturity onset diabetes of the young (MODY). The prevalence of MODY is difficult to access, and patients with MODY genes mutations are often identified during routine screening for other purposes. MODY2 was linked to glucokinase gene (GCK) mutations, and accounted for 8% to 56% of MODY, with the highest prevalence found in the southern Europe. The aim of this study was to examine the prevalence and nature of mutations in GCK gene in Iranian paients. We have screened GCK mutations by polymerase chain reaction (PCR);single stranded conformation polymorphism (SSCP) technique in 12 Iranian families with clinical diagnosis of MODY, included 30 patients (8 males and 22 females) and their 21 family members. PCR products with abnormal mobility in denaturing gradient gel electrophoresis (DGGE) were directly sequenced. We identified 6 novel mutations in GCK gene in Iranian families (corresponding to 36.6% prevalence). Our findings and the last study on MODY1 highlight that in addition to GCK, other MODY genes such as MODY3 and MODYX may play a significant role in diabetes characterized by monogenic autosomal dominant transmission. There is an important point that the genetic recognation can be used to pre-symptomatically identify family members at risk for developing MODY.
文摘Positive diagnosis of diabetes is currently easy, but typing diagnosis of diabetes still remains a challenge for every clinician. It is currently accepted that types of diabetes apart from T1D and T2D can expand and include several forms of diabetes mellitus;From gestational diabetes, to all forms of secondary diabetes mellitus due to medications, intercurrent disease but also infections, and finally monogenic diabetes, whose diagnosis is not always easy to establish. The aim is to reveal the difficulties that clinicians may face in the process of etiological diagnosis regarding the suspicion of this type of monogenic diabetes, through the study of 2 cases, in which MODY type diabetes was suspected. Today we recognize 17 different genetic mutations that can all lead to MODY diabetes, the most common mutation of which is GCK coding for the glucokinase, the real sensor of pancreatic Beta-cell. The truly stable glycemic profile, with an A1C ranging between 7% and 7.5%, confirmed with a TIR always above 70% and a good MAGE, but also the rarity of degenerative complications and pharmacological therapeutic abstention which can last for years, these would be the most striking clinical characteristics of a GCK MODY.
文摘报告1例青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)3型(MODY3)合并5型(MODY5)患者的临床特征、诊断及治疗,并复习相关文献。利用MODY(1~14型)基因外显子二代测序和Sanger测序验证MODY患者及其母亲,结合临床表型及基因检测结果,该患者诊断为MODY3合并MODY5,给予胰岛素及利格列汀治疗,观察血糖变化。临床医师应提高对MODY临床表型的认识,对于合并先天性胰腺和肾脏发育不全、高密度脂蛋白胆固醇升高,无自发酮症、胰岛素分泌缺陷,胰岛自身抗体阴性,无明显胰岛素抵抗,非肥胖的青少年糖尿病患者应行基因检测以筛查MODY,精准诊断并予以个体化治疗将有助于血糖水平达标及改善生活质量,并指导优化生育。
文摘肝细胞核因子1α(HNF1α)不仅是调节葡萄糖代谢的重要转录因子,还参与肝、胰等多个器官中蛋白质合成、物质代谢、增殖分化相关基因的表达调控。HNF1α突变或表达异常引发包括青少年糖尿病3型(maturity onset diabetes of young 3,MODY3)在内的多种代谢疾病。Ser249是HNF1α重要的功能位点,该位点受ATM蛋白激酶直接磷酸化修饰,并可能是ATM蛋白激酶影响葡萄糖代谢的效应靶点,也可能是共济失调毛细血管扩张症(ataxia telangiectasia,AT)患者糖代谢异常的致病靶点。为进一步研究Ser249磷酸化在体内的功能,本文构建人源野生型HNF1α转基因小鼠(WT小鼠)和HNF1αS249A转基因小鼠(S249A小鼠),对其基础代谢水平和葡萄糖代谢能力进行检测。相较于对照小鼠,S249A小鼠的多项基础代谢指标异常,WT小鼠未显示差异;但当小鼠接受刺激后,无论是注射葡萄糖,还是丙酮酸或胰岛素,相较于各自的对照小鼠,WT小鼠都表现出更强的反应性,而S249A小鼠的糖异生反应和胰岛素敏感性均未显示出差异。实时定量PCR结果表明,WT小鼠肝的多个糖代谢基因表达上调,但S249A小鼠肝中糖代谢基因上调幅度明显小于WT小鼠。本研究提示,HNF1αSer249突变导致小鼠糖代谢异常,可能与磷酸化修饰失调进而影响其转录活性有关。
文摘The disorder, Maturity Onset of Diabetes of the young (MODY) is a monogenic form of Non-Insulin dependent Diabetes Mellitus (NIDDM), characterized by autosomal dominant mode of inheritance and onset is usually before 25 years of age. Clinical studies of subjects with the different forms of MODY indicate that each is associated with a different defect in the normal pattern of glucose stimulated insulin secretion. MODY can result from mutations in any one of the six different genes, one of which encodes the glycolytic enzyme Glucokinase, associated with MO-DY2 and the other five encode transcription factors HNF4-alpha associated with MODY 1, HNF1-alpha associated with MODY 3, IPF with MODY 4, HNF1-Beta with MODY 5 and NeuroD1 with MO-DY6. Studies related to mutations in the MODY genes have led to a better understanding of the genetic causes of the Beta cell dysfunction as genetic factors plays a great role in this disorder. Objective: To investigate the mutation pattern in the different transcription factor genes with special reference to HNF1-alpha which are highly penetrant with 63% mutation carriers manifesting clinical diabetes by the age of 25 years. Hence study of mutation pattern in this gene is essential in our population i.e. Eastern Indian population. Our study is focused on HNF1-alpha related to MODY 3, which is the most common one. Methods: In our study enzyme amplification (PCR) of the 10 target exons of the said gene with simultaneous mutation detection in them by PCR-SSCP (Polymerase chain reaction-single strand conformational polymorphism) reaction analysis method was attempted by screening of exon 1 - 10 with respect to normal healthy controls without Diabetes Mellitus. The nature of the specific mutations was also determined by sequencing. Result: It was observed that maximum number of variations exist in exon 5 of HNF1-alpha gene which may be referred to as “Mutational Hotspot” in our Eastern Indian population. Conclusions: Since maximum number of variations exists in exon 5 of the said gene, hence one can initially go for exon5 followed by other exons, while screening for pathogenic MODY 3 mutations in the responsible gene by PCR-SSCP method.
文摘目的报道1例中国人葡萄糖激酶(glucokinase,GCK)新发基因突变导致青少年起病的成人型糖尿病2型(maturity-onset diabetes of the young,type 2,MODY2)家系,分析其遗传学特征及临床特点。方法对1例MODY2家系行基因测序、临床资料采集及分析。结果调查此家系成员共18人,其中先证者及其弟、父亲、叔父、堂弟等父系成员11人罹患糖尿病;先证者及其弟、父亲、叔父均存在GCK基因杂合同义突变(exon1:c.45G>A:p.K15K),生物信息学功能预测提示该突变可能影响mRNA剪接而致GCK功能受损,国内研究人群尚未见此突变报道;先证者及其弟糖化血红蛋白分别为6.49%、6.72%,空腹血糖分别为6.80、7.01 mmol/L,糖尿病自身抗体谱均为阴性,6~18个月随访示血糖水平保持稳定。结论此MODY2家系中GCK基因杂合同义突变(exon1:c.45G>A:p.K15K)为中国人新发突变位点,其临床表现为轻度、持续稳定的空腹高血糖及糖化血红蛋白升高,不应低估GCK基因同义突变的致病性。
基金This work was supported by grants from the National Natural Science Foundation of China (No. 30470813) Shanghai Scientific Committee (No. 02DJ14052-I).
文摘Background Mutations in the hepatocyte nuclear factor-lA gene cause the type 3 form of maturity-onset diabetes of the young （MODY3）. This study was undertaken to determine mutations and sequence variations of the HNF-1A gene in Chinese with familial early-onset and/or multiplex diabetes mellitus.
