BACKGROUND Neonatal hyperinsulinism can result from perinatal stress,genetic disorders,or syndromes,which can lead to persistent or intractable hypoglycemia in newborns.Mutations in the ABCC8 gene result in abnormal f...BACKGROUND Neonatal hyperinsulinism can result from perinatal stress,genetic disorders,or syndromes,which can lead to persistent or intractable hypoglycemia in newborns.Mutations in the ABCC8 gene result in abnormal functioning of potassium channel proteins in pancreaticβ-cells,leading to an overproduction of insulin and congenital hyperinsulinemia.CASE SUMMARY We report a case of a high-birth-weight infant with postnatal hypoglycemia and hyperinsulinemia,whose mother had pregestational diabetes mellitus with poor glycemic control and whose sister had a similar history at birth.Whole-exome sequencing revealed a new mutation in the ABCC8 gene in exon 8(c.1257T>G),which also occurred in his sister and mother;thus,the patient was diagnosed with neonatal hyperinsulinism with an ABCC8 mutation.With oral diazoxide treatment,the child’s blood glucose returned to normal,and the pediatrician gradually discontinued treatment because of the child’s good growth and development.CONCLUSION We report a new mutation locus in the ABCC8 gene.This mutation locus warrants attention for genetic disorders and long-term prognoses of hypoglycemic children.展开更多
ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and p...ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and patient outcomes has not been evaluated until now.Comparisons of ABCC8 expression between different tumors and normal tissues were evaluated by exploring publicly available datasets.The association between ABCC8 and tumor immune cell infiltration,diverse gene mutation characteristics,tumor mutation burden(TMB),and survival in LGG was also investigated in several independent datasets.Pathway enrichment analysis was conducted to search for ABCC8-associated signaling pathways.Through an online database,we found that ABCC8 expression in LGG was lower than in normal tissues.Then,the association of ABCC8 expression and immune cell infiltration in LGG was discussed.As we expected,the ABCC8 mRNA levels were negatively associated with non-T immune cell infiltration levels in all datasets.Consistently,TCGA_LGG RNA-seq data revealed that ABCC8 downregulated several non-T immune cell-associated signaling pathways in gene set enrichment analysis.Different ABCC8 expression groups showed diverse gene mutation characteristics and TMB.The high expression of ABCC8 was linked to improved survival of LGG patients.A pathway enrichment analysis of ABCC8-associated genes indicated that the GABAergic synapse signaling pathway might be involved in regulating immunity in LGG.Our findings show that ABCC8 reflects LGG tumor immunity and is an ideal prognostic biomarker for LGG.展开更多
BACKGROUND Transient neonatal diabetes mellitus(TNDM)is a rare form of diabetes mellitus that usually presents within the first 6 mo of life.Patients often enter remission within several months,although relapse can oc...BACKGROUND Transient neonatal diabetes mellitus(TNDM)is a rare form of diabetes mellitus that usually presents within the first 6 mo of life.Patients often enter remission within several months,although relapse can occur later in life.Mutations in the ABCC8 gene,which encodes the sulfonylurea receptor 1 of the ATP-sensitive potassium channel in pancreatic beta cells,are associated with TNDM and permanent neonatal diabetes.This study describes a novel de novo c.3880C>T heterozygous ABCC8 variant that causes TNDM and can be treated with sulfonylurea therapy.CASE SUMMARY We retrospectively analyzed 2 Chinese patients with TNDM who were diagnosed,treated,or referred for follow-up between September 2017 and September 2023.The patients were tested for mutations using targeted next-generation sequencing.Patients with neonatal diabetes mellitus caused by a c.3880C>T heterozygous missense variant in the ABCC8 gene have not been reported before.Both children had an onset of post-infectious diabetic ketoacidosis,which is worth noting.At a follow-up visit after discontinuing insulin injection,oral glyburide was found to be effective with no adverse reactions.CONCLUSION Early genetic testing of neonatal diabetes mellitus aids in accurate diagnosis and treatment and helps avoid daily insulin injections that may cause pain.展开更多
新生儿糖尿病和高胰岛素症最常见的致病原因之一是三磷酸腺苷结合盒转运蛋白亚家族C成员8(adenosine triphosphate binding cassette subfamily C member 8,ABCC8)和钾内向整流通道亚家族J成员11(potassium inwardly rectifying channel...新生儿糖尿病和高胰岛素症最常见的致病原因之一是三磷酸腺苷结合盒转运蛋白亚家族C成员8(adenosine triphosphate binding cassette subfamily C member 8,ABCC8)和钾内向整流通道亚家族J成员11(potassium inwardly rectifying channel subfamily J member 11,KCNJ11)基因突变,这些基因编码β细胞三磷酸腺苷(adenosine triphosphate,ATP)敏感钾通道的亚基,而β细胞ATP敏感钾通道是葡萄糖刺激胰岛素分泌途径的关键组成部分。ABCC8基因突变所导致的临床表型多种多样,遗传学情况也纷繁复杂。新生儿暂时性糖尿病、新生儿永久性糖尿病、青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)可因ABCC8基因的功能增强性突变引起,通常为显性遗传,但也包含部分隐性遗传和复合杂合突变。而ABCC8基因功能失活性突变可引起高胰岛素性低血糖,遗传学类型既包含显性遗传又包含隐性遗传。同时部分家系中具有相同突变类型的患者间却存在较大的临床异质性。此外,部分患者生命早期可表现为高胰岛素血症,当胰岛β细胞凋亡或细胞功能耗竭后,疾病类型反而转变为MODY。本综述将讨论ABCC8基因突变所致的相关糖代谢疾病发病机制、临床表现及治疗,阐述其临床异质性,以期增强临床医生对该类疾病的了解认识。展开更多
Background KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from B...Background KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from Beijing, whether the genetic variants in these four genes were associated with genetic predisposition to type 2 diabetes. Methods We studied the association of four representative SNPs in KCNJ11, ABCC8, PPARG, and HNF4A by genotyping them using ABI SNaPshot Multiplex System in 400 unrelated type 2 diabetic patients and 400 unrelated normoglycaemic subjects. Results rs5219（E23K） in KCNJ11 was associated with genetic susceptibility to type 2 diabetes （OR=1.400 with 95% CI 1.117 1.755, P=0.004 under an additive model, 0R=1.652 with 95% CI 1.086 2.513, P=0.019 under a recessive model, and OR=1.521 with 95% Cl 1.089 2.123, P=0.014 under a dominant model） after adjusting for sex and body mass index （BMI）. We did not find evidence of association for ABCC8 rs1799854, PPARG rs1801282 （Pro12Ala） and HNF4A rs2144908. Genotype-phenotype correlation analysis revealed that rs1799854 in ABCC8 was associated with 2-hour postprandial insulin secretion （P=0.005） after adjusting for sex, age and BMI. Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin （P=-0.004 under an additive model for rs2144908; and P=0.001 under a dominant model for rs2144908） after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala. Conclusions Our study replicated the association of rs5219 in KCNJ11 with type 2 diabetes in Chinese Han population in Beijing. And we also observed that ABCC8 as well as the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion.展开更多
文摘BACKGROUND Neonatal hyperinsulinism can result from perinatal stress,genetic disorders,or syndromes,which can lead to persistent or intractable hypoglycemia in newborns.Mutations in the ABCC8 gene result in abnormal functioning of potassium channel proteins in pancreaticβ-cells,leading to an overproduction of insulin and congenital hyperinsulinemia.CASE SUMMARY We report a case of a high-birth-weight infant with postnatal hypoglycemia and hyperinsulinemia,whose mother had pregestational diabetes mellitus with poor glycemic control and whose sister had a similar history at birth.Whole-exome sequencing revealed a new mutation in the ABCC8 gene in exon 8(c.1257T>G),which also occurred in his sister and mother;thus,the patient was diagnosed with neonatal hyperinsulinism with an ABCC8 mutation.With oral diazoxide treatment,the child’s blood glucose returned to normal,and the pediatrician gradually discontinued treatment because of the child’s good growth and development.CONCLUSION We report a new mutation locus in the ABCC8 gene.This mutation locus warrants attention for genetic disorders and long-term prognoses of hypoglycemic children.
基金supported by the Scientific and Technological Innovation Program for Clinical Medicine of Jinan(202019132)to LIPING GONG.
文摘ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and patient outcomes has not been evaluated until now.Comparisons of ABCC8 expression between different tumors and normal tissues were evaluated by exploring publicly available datasets.The association between ABCC8 and tumor immune cell infiltration,diverse gene mutation characteristics,tumor mutation burden(TMB),and survival in LGG was also investigated in several independent datasets.Pathway enrichment analysis was conducted to search for ABCC8-associated signaling pathways.Through an online database,we found that ABCC8 expression in LGG was lower than in normal tissues.Then,the association of ABCC8 expression and immune cell infiltration in LGG was discussed.As we expected,the ABCC8 mRNA levels were negatively associated with non-T immune cell infiltration levels in all datasets.Consistently,TCGA_LGG RNA-seq data revealed that ABCC8 downregulated several non-T immune cell-associated signaling pathways in gene set enrichment analysis.Different ABCC8 expression groups showed diverse gene mutation characteristics and TMB.The high expression of ABCC8 was linked to improved survival of LGG patients.A pathway enrichment analysis of ABCC8-associated genes indicated that the GABAergic synapse signaling pathway might be involved in regulating immunity in LGG.Our findings show that ABCC8 reflects LGG tumor immunity and is an ideal prognostic biomarker for LGG.
基金Supported by the Department of Science and Technology of Henan Province,China,No.222102310461。
文摘BACKGROUND Transient neonatal diabetes mellitus(TNDM)is a rare form of diabetes mellitus that usually presents within the first 6 mo of life.Patients often enter remission within several months,although relapse can occur later in life.Mutations in the ABCC8 gene,which encodes the sulfonylurea receptor 1 of the ATP-sensitive potassium channel in pancreatic beta cells,are associated with TNDM and permanent neonatal diabetes.This study describes a novel de novo c.3880C>T heterozygous ABCC8 variant that causes TNDM and can be treated with sulfonylurea therapy.CASE SUMMARY We retrospectively analyzed 2 Chinese patients with TNDM who were diagnosed,treated,or referred for follow-up between September 2017 and September 2023.The patients were tested for mutations using targeted next-generation sequencing.Patients with neonatal diabetes mellitus caused by a c.3880C>T heterozygous missense variant in the ABCC8 gene have not been reported before.Both children had an onset of post-infectious diabetic ketoacidosis,which is worth noting.At a follow-up visit after discontinuing insulin injection,oral glyburide was found to be effective with no adverse reactions.CONCLUSION Early genetic testing of neonatal diabetes mellitus aids in accurate diagnosis and treatment and helps avoid daily insulin injections that may cause pain.
文摘新生儿糖尿病和高胰岛素症最常见的致病原因之一是三磷酸腺苷结合盒转运蛋白亚家族C成员8(adenosine triphosphate binding cassette subfamily C member 8,ABCC8)和钾内向整流通道亚家族J成员11(potassium inwardly rectifying channel subfamily J member 11,KCNJ11)基因突变,这些基因编码β细胞三磷酸腺苷(adenosine triphosphate,ATP)敏感钾通道的亚基,而β细胞ATP敏感钾通道是葡萄糖刺激胰岛素分泌途径的关键组成部分。ABCC8基因突变所导致的临床表型多种多样,遗传学情况也纷繁复杂。新生儿暂时性糖尿病、新生儿永久性糖尿病、青少年起病的成人型糖尿病(maturity-onset diabetes of the young,MODY)可因ABCC8基因的功能增强性突变引起,通常为显性遗传,但也包含部分隐性遗传和复合杂合突变。而ABCC8基因功能失活性突变可引起高胰岛素性低血糖,遗传学类型既包含显性遗传又包含隐性遗传。同时部分家系中具有相同突变类型的患者间却存在较大的临床异质性。此外,部分患者生命早期可表现为高胰岛素血症,当胰岛β细胞凋亡或细胞功能耗竭后,疾病类型反而转变为MODY。本综述将讨论ABCC8基因突变所致的相关糖代谢疾病发病机制、临床表现及治疗,阐述其临床异质性,以期增强临床医生对该类疾病的了解认识。
文摘Background KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from Beijing, whether the genetic variants in these four genes were associated with genetic predisposition to type 2 diabetes. Methods We studied the association of four representative SNPs in KCNJ11, ABCC8, PPARG, and HNF4A by genotyping them using ABI SNaPshot Multiplex System in 400 unrelated type 2 diabetic patients and 400 unrelated normoglycaemic subjects. Results rs5219（E23K） in KCNJ11 was associated with genetic susceptibility to type 2 diabetes （OR=1.400 with 95% CI 1.117 1.755, P=0.004 under an additive model, 0R=1.652 with 95% CI 1.086 2.513, P=0.019 under a recessive model, and OR=1.521 with 95% Cl 1.089 2.123, P=0.014 under a dominant model） after adjusting for sex and body mass index （BMI）. We did not find evidence of association for ABCC8 rs1799854, PPARG rs1801282 （Pro12Ala） and HNF4A rs2144908. Genotype-phenotype correlation analysis revealed that rs1799854 in ABCC8 was associated with 2-hour postprandial insulin secretion （P=0.005） after adjusting for sex, age and BMI. Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin （P=-0.004 under an additive model for rs2144908; and P=0.001 under a dominant model for rs2144908） after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala. Conclusions Our study replicated the association of rs5219 in KCNJ11 with type 2 diabetes in Chinese Han population in Beijing. And we also observed that ABCC8 as well as the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion.
