上海地区早发2型糖尿病家系患者配对盒4基因Arg192Ser突变的研究
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摘要
目的探讨早发T2DM家系患者配对盒4(PAX4)基因外显子3,5及9的多态及临床特点。方法选取上海地区96个家系中96例早发T2DM且有糖尿病家族史的患者(T2DM组)和96名OGTT正常、≥50岁且无糖尿病家族史的对照者(NGT组)。PCR测定两组人群PAX4基因突变/变异情况,统计分析基因型、等位基因分布频率及临床特点。结果两组Arg192Ser多态基因型(Arg/Arg、Arg/Ser、Ser/Ser)及等位基因(Arg、Ser)频率比较,差异有统计学意义(P<0. 01),T2DM组Ser/Ser基因型及Ser等位基因频率高于NGT组[(99. 0%vs 1. 0%),(99. 0%vs 1. 0%),P<0. 01]。T2DM组检出PAX4基因新的错义突变Arg192Ser(C→A),导致第192位氨基酸由精氨酸突变成丝氨酸。外显子3未发现多态,PAX4基因外显子9 His321Pro(A→C)多态可能不是早发T2DM的遗传易感标志。结论 PAX4基因Arg192Ser突变可能是上海人群早发T2DM的易感标志。
Objective To investigate the polymorphisms in exon 3, 5 and 9 in paired box4(PAX4)gene and their clinical characteristics in early onset type 2 diabetes(T2DM) families. Methods A total of192 subjects in Shanghai were enrolled in this study and divided into two groups: patients with early onset T2DM and T2DM family history(T2DM group, n = 96), and healthy subjects≥50 years old, with normal OGTT and no family history of T2DM(NGT group, n= 96). PCR-direct sequencing was used to detect polymorphism in exon 3,5 and 9 in PAX4 gene in all the subjects. Genotypes,allele frequencies and clinical characteristics were compared between the two groups. Results Genotypes(Arg/Arg, Arg/Ser, Ser/Ser)and allele frequency(Arg, Ser) of Arg192 Ser were significant different(P<0.01) between NGT and T2DM group(P<0. 01). Ser/Ser genotype and Ser allele frequencies were higher in T2DM group than in NGT group(genotype ratio was 99.0% vs 1.0%, allele ratio was 99.0% vs 1.0%, P<0.01). A new missense mutation Arg192 Ser(C→A) in PAX4 gene was detected in T2DM group, leding to the mutation of arginine(Arg) to serine(Ser). No polymorphism was found in exon 3. The polymorphism of His321 Pro(A→C) of exon 9 in PAX4 gene may not be a genetic candidate of the early onset of T2DM. Conclusion The Arg192 Ser in PAX4 gene may be a genetic candidate of early onset T2DM in Shanghai.
Objective To investigate the polymorphisms in exon 3, 5 and 9 in paired box4(PAX4)gene and their clinical characteristics in early onset type 2 diabetes(T2DM) families. Methods A total of192 subjects in Shanghai were enrolled in this study and divided into two groups: patients with early onset T2DM and T2DM family history(T2DM group, n = 96), and healthy subjects≥50 years old, with normal OGTT and no family history of T2DM(NGT group, n= 96). PCR-direct sequencing was used to detect polymorphism in exon 3,5 and 9 in PAX4 gene in all the subjects. Genotypes,allele frequencies and clinical characteristics were compared between the two groups. Results Genotypes(Arg/Arg, Arg/Ser, Ser/Ser)and allele frequency(Arg, Ser) of Arg192 Ser were significant different(P<0.01) between NGT and T2DM group(P<0. 01). Ser/Ser genotype and Ser allele frequencies were higher in T2DM group than in NGT group(genotype ratio was 99.0% vs 1.0%, allele ratio was 99.0% vs 1.0%, P<0.01). A new missense mutation Arg192 Ser(C→A) in PAX4 gene was detected in T2DM group, leding to the mutation of arginine(Arg) to serine(Ser). No polymorphism was found in exon 3. The polymorphism of His321 Pro(A→C) of exon 9 in PAX4 gene may not be a genetic candidate of the early onset of T2DM. Conclusion The Arg192 Ser in PAX4 gene may be a genetic candidate of early onset T2DM in Shanghai.
引文
[1] Fajans SS, Bell GI, Polonsky KS,et al. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med,2001,345:971-980.
[2] Sosa-Pineda B, Chowdhury K, Torres M,et al. The PAX4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature,1997,386:399-402.
[3] Larsson LI, St-Onge L, Hougaard DM, et al. Pax 4 and 6 regulate gastrointestinal endocrine cell development. Mech Dev,1998,79:153-159.
[4] Sosa-Pineda B. The gene PAX4 is an essential regulator of pancreatic beta-cell development, Mol Cells, 2004,18:289-294.
[5] Shimajiri Y,Sanke T,Furuta H,et al. A missense mutation of PAX4 gene(R121W)is associated with type 2 diabetes in Japanese. Diabetes, 2001, 50:2864-2869.
[6]Tokuyama Y,Matsui K,Ishizuka T,et al. The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus. Metabolism,2006,55:213-216.
[7] Plengvidhya N, Kooptiwut S, Songtawee N, et al. PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocrinol Metab,2007,92:2821-2826
[8] Lang D,Powell SK,Plummer RS,et al. PAX genes:Roles in development,pathophysiology, and cancer. Biochem Pharmacol,2007,73:1-14.
[9] Greenwood AL,Li S, Jones K,et al. Notch signaling reveals developmental plasticity of PAX4(+)pancreatic endocrine progenitors and shunts them to a duct fate. Mech Dev,2007,124:97-107.
[10] Wang J,Elghazi L, Parker SE,et al. The concerted activities of PAX4 and Nkx2. 2 are essential to initiate pancreaticβ-cell differentiation. Developmental Biology,2004,266:178-189.
[11] Jo W, Endo M, Ishizu K, et al. A novel PAX4 mutation in a Japanese patient with maturity-onset diabetes of the young. Tohoku J Exp Med,2011,223:113-118.
[12] Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:Possible link to beta cell regenerative capacity. Diabetologia, 2005,48:900-905.
[2] Sosa-Pineda B, Chowdhury K, Torres M,et al. The PAX4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature,1997,386:399-402.
[3] Larsson LI, St-Onge L, Hougaard DM, et al. Pax 4 and 6 regulate gastrointestinal endocrine cell development. Mech Dev,1998,79:153-159.
[4] Sosa-Pineda B. The gene PAX4 is an essential regulator of pancreatic beta-cell development, Mol Cells, 2004,18:289-294.
[5] Shimajiri Y,Sanke T,Furuta H,et al. A missense mutation of PAX4 gene(R121W)is associated with type 2 diabetes in Japanese. Diabetes, 2001, 50:2864-2869.
[6]Tokuyama Y,Matsui K,Ishizuka T,et al. The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus. Metabolism,2006,55:213-216.
[7] Plengvidhya N, Kooptiwut S, Songtawee N, et al. PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocrinol Metab,2007,92:2821-2826
[8] Lang D,Powell SK,Plummer RS,et al. PAX genes:Roles in development,pathophysiology, and cancer. Biochem Pharmacol,2007,73:1-14.
[9] Greenwood AL,Li S, Jones K,et al. Notch signaling reveals developmental plasticity of PAX4(+)pancreatic endocrine progenitors and shunts them to a duct fate. Mech Dev,2007,124:97-107.
[10] Wang J,Elghazi L, Parker SE,et al. The concerted activities of PAX4 and Nkx2. 2 are essential to initiate pancreaticβ-cell differentiation. Developmental Biology,2004,266:178-189.
[11] Jo W, Endo M, Ishizu K, et al. A novel PAX4 mutation in a Japanese patient with maturity-onset diabetes of the young. Tohoku J Exp Med,2011,223:113-118.
[12] Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:Possible link to beta cell regenerative capacity. Diabetologia, 2005,48:900-905.