为了解我国奶牛群中牛瓜氨酸血症(Citrullinemia,CN)、尿苷酸合酶缺乏症(Deficiency of uridine monophophate synthase,DUMPS)的携带和发生情况,根据已报道的ASS、UMPS基因核苷酸序列,设计2对引物建立了相应PCR-RFLP检测方法,并对表型...为了解我国奶牛群中牛瓜氨酸血症(Citrullinemia,CN)、尿苷酸合酶缺乏症(Deficiency of uridine monophophate synthase,DUMPS)的携带和发生情况,根据已报道的ASS、UMPS基因核苷酸序列,设计2对引物建立了相应PCR-RFLP检测方法,并对表型正常的436头荷斯坦母牛及93头荷斯坦公牛进行检测。结果共检出CN、DUMPS杂合牛分别为8和6头,携带率分别为1.55%,1.17%,其中CN、DUMPS公牛杂合子分别为2和1头。展开更多
AIM:To determine the prevalence of SLC25A13 mutations in the Thai population.METHODS:A total of 1537 subjects representing the Thai population were screened for a novel pathologic allele p.Met1?(c.2T>C)and six prev...AIM:To determine the prevalence of SLC25A13 mutations in the Thai population.METHODS:A total of 1537 subjects representing the Thai population were screened for a novel pathologic allele p.Met1?(c.2T>C)and six previously known common SLC25A13 mutations:[Ⅰ](c.851_854delGTAT),[Ⅱ](g.IVS11+1G>A),[Ⅲ](c.1638_1660dup),[Ⅳ](p.S225X),[Ⅴ](IVS13+1G>A),and[XIX](g.IVS16ins3kb)using a newly developed TaqMan and established HybProbe assay,respectively.Sanger sequencing was employed for specimens showing an aberrant peak to confirm the targeted mutation as well as the unknown aberrant peaks detected.Frequencies of the mutations identified were compared in each region.Carrier frequency and disease prevalence of citrin deficiency caused by SCL25A13 mutations were estimated.RESULTS:p.Met1?was identified in the heterozygous state in 85 individuals,giving a carrier frequency of1/18,which suggests possible selective advantage of this variant.The question of p.Met1?homozygote lethality remains unanswered which may serve as an explanation as to why this homozygote has yet to be identified in patients/controls even with high allele frequency.The p.Met1?mutation has rarely been studied in populations other than Thai and Chinese;therefore,may have been overlooked.Development of the TaqMan assay in the present study would allow a simple,rapid,and cost-effective method for mass screening.Heterozygous mutations:[XIX]and[Ⅰ]were identified in 17 individuals,giving a carrier rate of 1/90 and a calculated homozygote rate of 1/33000.Two novel variants,g.IVS11+17C>G and c.1311C>T,of unknown clinical significance were identified at low frequency.CONCLUSION:This study highlighted the current underestimation of citrin deficiency and suggests the possible selective advantage of the p.Met1?allele.展开更多
The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitocho...The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.展开更多
Kazal-type serine protease inhibitor is one of the most important and widely distributed protease inhibitor families.Pancreatic secretory trypsin inhibitor(PSTI),also known as serine protease inhibitor Kazal typeⅠ(SP...Kazal-type serine protease inhibitor is one of the most important and widely distributed protease inhibitor families.Pancreatic secretory trypsin inhibitor(PSTI),also known as serine protease inhibitor Kazal typeⅠ(SPINK1),binds rapidly to trypsin,inhibits its activity and is likely to protect the pancreas from prematurely activated trypsinogen.Therefore,it is an important factor in the onset of pancreatitis.Recent studies found that PSTI/SPINK1 is also involved in self-regulation of acinar cell phagocytosis,proliferation and growth of a variety of cell lines.In addition,it takes part in the response to inflammatory factor or injury and is highly related to adult type Ⅱ citrullinemia.展开更多
Citrin deficiency,autosomal recessive disorder,caused by mutation of SLC25A13 gene on chromosome 7q21.3 has two major phenotypes:neonatal intrahepatic cholestatic hepatitis(NICCD)and adult-onset type Ⅱ citrullinemia(...Citrin deficiency,autosomal recessive disorder,caused by mutation of SLC25A13 gene on chromosome 7q21.3 has two major phenotypes:neonatal intrahepatic cholestatic hepatitis(NICCD)and adult-onset type Ⅱ citrullinemia(CTLN2).So far,we have identified 52 SLC25A13 mutations and diagnosed the patients not only in Japan(166 CTLN2 and 238 NICCD) but also in other countries.We have detected 76 Chinese,13 Korean and 15 Vietnamese patients with the same mutations as Japanese,and 13 patients(from Israel,UK,USA or Czech)with mutations different from those found in Japanese,indicating a wide distribution of citrin deficiency.DNA diagnoses of 13 known SLC25A13 mutations revealed that the carrier frequency was high in East Asian populations:Chinese(73/4 600=1/63),Japanese(21/1 372=1/65) and Korean(25/2 690=1/108),suggesting that near by 100 000 East Asians are homozygotes.It is important to find out patients with citrin deficiency,to treat them,and to prevent onset of severe CTLN2.展开更多
文摘为了解我国奶牛群中牛瓜氨酸血症(Citrullinemia,CN)、尿苷酸合酶缺乏症(Deficiency of uridine monophophate synthase,DUMPS)的携带和发生情况,根据已报道的ASS、UMPS基因核苷酸序列,设计2对引物建立了相应PCR-RFLP检测方法,并对表型正常的436头荷斯坦母牛及93头荷斯坦公牛进行检测。结果共检出CN、DUMPS杂合牛分别为8和6头,携带率分别为1.55%,1.17%,其中CN、DUMPS公牛杂合子分别为2和1头。
基金Supported by A joint grant from Mahidol University Faculty of Science and Ramathibodi Hospital Faculty of Medicine (Jensen LT and Wattanasirichaigoon D)Mahidol University (Wattanasirichaigoon D: 49/2556)+2 种基金the Pharmacogenomics Project,the collaborative project from the Thailand Center of Excellence for Life Science and Mahidol University to Sukasem Cthe Medical Scholars Program of Mahidol University (Wongkittichote P)a recipient (Wattanasirichaigoon D) of Research Career Development Award,Faculty of Medicine Ramathibodi Hospital
文摘AIM:To determine the prevalence of SLC25A13 mutations in the Thai population.METHODS:A total of 1537 subjects representing the Thai population were screened for a novel pathologic allele p.Met1?(c.2T>C)and six previously known common SLC25A13 mutations:[Ⅰ](c.851_854delGTAT),[Ⅱ](g.IVS11+1G>A),[Ⅲ](c.1638_1660dup),[Ⅳ](p.S225X),[Ⅴ](IVS13+1G>A),and[XIX](g.IVS16ins3kb)using a newly developed TaqMan and established HybProbe assay,respectively.Sanger sequencing was employed for specimens showing an aberrant peak to confirm the targeted mutation as well as the unknown aberrant peaks detected.Frequencies of the mutations identified were compared in each region.Carrier frequency and disease prevalence of citrin deficiency caused by SCL25A13 mutations were estimated.RESULTS:p.Met1?was identified in the heterozygous state in 85 individuals,giving a carrier frequency of1/18,which suggests possible selective advantage of this variant.The question of p.Met1?homozygote lethality remains unanswered which may serve as an explanation as to why this homozygote has yet to be identified in patients/controls even with high allele frequency.The p.Met1?mutation has rarely been studied in populations other than Thai and Chinese;therefore,may have been overlooked.Development of the TaqMan assay in the present study would allow a simple,rapid,and cost-effective method for mass screening.Heterozygous mutations:[XIX]and[Ⅰ]were identified in 17 individuals,giving a carrier rate of 1/90 and a calculated homozygote rate of 1/33000.Two novel variants,g.IVS11+17C>G and c.1311C>T,of unknown clinical significance were identified at low frequency.CONCLUSION:This study highlighted the current underestimation of citrin deficiency and suggests the possible selective advantage of the p.Met1?allele.
文摘The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.
基金Supported by the National Basic Research 973 Pre-research Program of China,No.2006CB708506
文摘Kazal-type serine protease inhibitor is one of the most important and widely distributed protease inhibitor families.Pancreatic secretory trypsin inhibitor(PSTI),also known as serine protease inhibitor Kazal typeⅠ(SPINK1),binds rapidly to trypsin,inhibits its activity and is likely to protect the pancreas from prematurely activated trypsinogen.Therefore,it is an important factor in the onset of pancreatitis.Recent studies found that PSTI/SPINK1 is also involved in self-regulation of acinar cell phagocytosis,proliferation and growth of a variety of cell lines.In addition,it takes part in the response to inflammatory factor or injury and is highly related to adult type Ⅱ citrullinemia.
基金Grant-in-Aids for Scientific Research(B:No.16390100 and 19390096)Asia-Africa Scientific Platform Program(AASPP)+1 种基金the Japan Society for the Promotion of Science(JSPS)a Grant for Child Health and Development(17-2 and 20-2)the Ministry of Health,Labour and Welfare in Japan
文摘Citrin deficiency,autosomal recessive disorder,caused by mutation of SLC25A13 gene on chromosome 7q21.3 has two major phenotypes:neonatal intrahepatic cholestatic hepatitis(NICCD)and adult-onset type Ⅱ citrullinemia(CTLN2).So far,we have identified 52 SLC25A13 mutations and diagnosed the patients not only in Japan(166 CTLN2 and 238 NICCD) but also in other countries.We have detected 76 Chinese,13 Korean and 15 Vietnamese patients with the same mutations as Japanese,and 13 patients(from Israel,UK,USA or Czech)with mutations different from those found in Japanese,indicating a wide distribution of citrin deficiency.DNA diagnoses of 13 known SLC25A13 mutations revealed that the carrier frequency was high in East Asian populations:Chinese(73/4 600=1/63),Japanese(21/1 372=1/65) and Korean(25/2 690=1/108),suggesting that near by 100 000 East Asians are homozygotes.It is important to find out patients with citrin deficiency,to treat them,and to prevent onset of severe CTLN2.
