伴有红细胞和血小板异常的植物固醇血症临床及发病机制的研究
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摘要
巨大血小板病(giant platelet disorders,GPD)是一组异质性疾病,表现为血小板减少,巨大血小板和不同程度的出血。近年来,随着实验室检测技术的进展,新的巨大血小板病不断地被发现,但至今还有相当多的病例不能被分类和鉴定,易造成误诊。在临床实际工作中,我们发现一些巨大血小板病不是血小板本身的病变,而是其它疾病的一种特殊表型。最近我们遇到了一种罕见的病例,患者除表现巨大血小板减少外,还表现为红细胞异形、溶血性贫血和血浆植物固醇明显增高。对这种伴有巨大血小板的特殊病例进行深入细致的研究,有助于临床医生正确的认识此类疾病,及时地作出诊断、鉴别诊断和治疗,并为将来的进一步研究提供理论基础。
目的巨大血小板减少与溶血性贫血共存在血液病中十分罕见,而且人们对其认识不清。一些血液病表现为溶血性贫血伴血小板减少,如Evan's综合征、血栓性血小板减少性紫癜等,但它们的血小板体积不大。1969年由Ducrou等提出的地中海口形红细胞增多症/地中海巨大血小板减少症,临床上表现为口形红细胞增多性溶血性贫血和巨大血小板,但仅见于澳大利亚的Adelaide地区,未见于其它地中海地区,其病因和发病机制不清。1974年Bhaltacharyya等首次报道了植物固醇血症(又称β-谷固醇血症),它是一种罕见的常染色体隐性遗传性脂质代谢性疾病。特征是植物固醇特别是谷固醇在血液和组织中积聚,从而引起黄色瘤,早发性冠心病、动脉硬化、关节炎等。2005年Rees等首次报道了表现为口形红细胞增多和巨大血小板的植物固醇血症。最近,我们发现了来自江苏盐城的一个家庭的3个孩子自幼表现为溶血性贫血和巨大血小板减少,与地中海巨大血小板减少症相似,但随着年龄的增长逐渐出现皮肤的黄色瘤。为了了解这种血液学异常与植物固醇之间的关系,为了阐明此类疾病发生的分子机制以及将此类疾病与其它巨大血小板病区别开来,我们对此家系的临床、生物化学和分子生物学特征进行了研究。
方法第1部分建立特异精确的血浆植物固醇测定方法,以便植物固醇血症的诊断。制备谷固醇、豆固醇和二氢胆固醇标准溶液及收集患者、他们父母和10名正常人非抗凝禁食血2ml。100μl血清或标准溶液用1mol/L氢氧化钾乙醇溶液皂化,正己烷溶液提取,苯甲酰氯溶液衍生。衍生物再用正己烷溶液提取,然后在氮气流下挥发蒸干。非挥发物用100μl四氢呋喃:乙腈(1:1)溶解液溶解后,取10μl注入高效液相色谱(HPLC)进行测定。HPLC仪为美国Agilent1100系统,层析柱为Diamonsil C_(18),流动相为乙腈和异丙醇(75:25,v/v),流速为1ml/min。在235nm的波长下测定紫外吸收值。第2部分分析一个植物固醇血症家系的临床特征。光学显微镜观察红细胞和血小板形态。比浊法测定血小板聚集。流式细胞术检测血小板膜糖蛋白(GP)。PCR法扩增ABCG5和ABCG8基因的所有外显子和侧翼序列,DNA测序确定基因异常,限制性内切酶(BfaⅠ)分析该家系及70名正常人相应序列的PCR产物。第3部分用HPLC法检测3名患者、他们父母和6例正常人红细胞膜的固醇含量。将谷固醇与红细胞在体外进行孵育,观察正常人红细胞形态变化并检测其渗透脆性。
结果第1部分植物固醇血症患者血浆谷甾醇和豆甾醇浓度明显高于正常人均值。他们父母的谷固醇和二氢胆固醇浓度比正常人均值轻度增高,而豆固醇未见增高。第2部分3名患者临床上主要表现巨大血小板和红细胞形态异常,如球形、口形红细胞和靶形细胞。红细胞渗透脆行增加。出血时间延长、对瑞斯托霉素诱导聚集反应降低。他们血浆谷固醇、豆固醇和二氢胆固醇浓度明显增高而总胆固醇浓度正常。发现在ABCG5基因外显子1中18802位碱基发生C→T突变,导致22位的谷氨酰胺(Q)变为终止密码子。3名患者均为纯合子,其父母及两个亲属为杂合子。对ABCG8基因测序未见异常。限制性内酶BfaⅠ分析70名正常人相应序列的PCR产物未发现相同的基因突变。第3部分3名患者红细胞膜的谷固醇、豆固醇和二氢胆固醇浓度明显增高。谷固醇与红细胞孵育后,红细胞异形明显,可见口形、球形红细胞和靶形细胞。谷固醇组红细胞渗透脆性较对照组升高。
结论1.本研究采用改良的HPLC法对血浆植物固醇进行定量检测,该法具有简便快速,灵敏度高,需血样品量小及分离效果好等优点,为植物固醇血症的诊断提供了一种切实可行的检测方法。2.血细胞是血浆植物固醇毒性作用的一个靶子;显著增高的血浆植物固醇导致了红细胞和血小板的异常;红细胞和血小板的异常是植物固醇血症的一种特殊的表型;伴有巨大血小板和(或)难以解释的溶血性贫血的患者需与植物固醇血症鉴别。3.ABCG5基因外显子1上的一个新的无义突变构成了伴有红细胞和血小板异常的植物固醇血症的分子基础。此突变是国际尚未报道的一个新的突变。4.植物固醇血症患者不仅血浆植物固醇含量增加,而且红细胞膜上的植物固醇含量也增加:血浆植物固醇含量的增加对红细胞形态和渗透脆性有明显的影响。
Giant platelet disorders are a heterogeneous group of diseases with thrombocytopenia,large platelets and variable hemorrhagic phenomena,which are from either primary platelet disorders or a specific phenotype of other conditions.With the development of laboratory technology,some novel platelet disorders are constantly discovered.However,to date there are a lot of cases which are not classified and identified.Recently,we found a rare case with macrothrombocytopenia,abnormal erythrocyte shape,hemolysis and increased plasma levels of phytosterols.Although rare, the further research on particular disorders with giant platelets will help clinicians correctly understand,diagnose and treat them.This work may provide a valuable reference for clinicians.
Objective
The combination of macrothrombocytopenia and hemolysis is an unusually and poorly understood hematological condition.Some of hematological diseases present with hemolysis and thrombocytopenia,such as Evan's syndrome,thrombotic thrombocytopenic purpura.In none of these conditions were the platelets large. Mediterranean stomatocytosis/macrothrombocytopenia was first described in individuals of Mediterranean origin in Adelaide,Australia by Ducrou in 1969.No reports arose from any other Australian centre,nor from any Mediterranean country. The exact nature of this condition that combines stomatocytic hemolysis with the presence of very large platelets has never been elucidated.Phytosterolaemia is a rare autosomal recessive disorder,first described by Bhattacharyya in 1974,characterized by hyperabsorption of plant sterols from the intestine and inability to excrete these sterols into the bile.As a consequence,affected individuals show very high levels of plant sterols.The patients suffer from tendon and tuberous xanthomas and premature atherosclerosis and coronary artery disease.Rees first reported phytosterolaemia associated stomatocytic hemolysis and macrothrombocytopenia in 2005.Recently,we found a family with phytosterolaemia from Jiangsu province,China,all children of which showed hemolysis with very large platelets,conforming to the description of Mediterranean macrothrombocytopenia.However,since the age of over10 years they had noticed enlarging tendon and tuberous xanthomas that began on the both elbows, and then in hips.To analyze the relationship between hematological abnormalities and phytosterolaemia,elucidate the molecular mechanisms of this disorder and distinguish it from other syndromes associated with giant platelets,in this study,we characterized the clinical,biochemical and molecular genetic features of a Chinese family with phytosterolaemia that mainly manifested hematological abnormalities.
Methods
PartⅠ:A simple,rapid and accurate method to separate and quantify serum sterols was performed by high performance liquid chromatography(HPLC).No coagulant fasting blood samples were collected from the affected patients,their parents,other two family members and 10 normal volunteers.Briefly,100μl of serum,or 10 mg/dl stigmasterol,2.5 mg/dl cholestanol and 1.5 mg/dl sitosterol standard was placed respectively in a screw-capped test-tube,and then 1ml of 1M ethanolic potassium hydroxide was added.After vigorous stirring,the saponified mixture was allowed to stand for 1h at 80℃,and then 1ml of water was added.The unsaponifiable material was extracted with two-2ml portions of hexane.The extracts were evaporated under a stream of nitrogen.The sterols in the extracts were converted into benzoate derivatives with benzoyl chloride,and then re-extracted with hexane.The hexane layer was again evaporated under nitrogen.Finally,the residue was dissolved in 0.1 ml of acetonitrile-tetrahydrofuran(1:1,v/v),and 10μl were injected into the HPLC system. The instrument was an Agilent 1100 HPLC system,equipped with a Diamonsil C_(18) column which was maintained at 30℃.The solvent was acetonitrile-isopropylalcohol (75:25,v/v) at a flow-rate of 1 ml/min.Steryl benzoates were detected by their absorbance at 235 nm.
PartⅡ:The clinical features of the affected patients in this family were analyzed. Erythrocyte and platelet morphology was observed under light microscope.Platelet aggregation was measured turbidometrically.Platelet glycoproteins(GPs) were analyzed using flow cytometry.Their plasma sterol levels were measured by HPLC method.ABCG5 and ABCG8 genes sequencing was searched for the mutation. Restriction endonuclease analysis was used for the PCR products of exon 1 of ABCG5 and its flanking regions of the family members and 70 healthy volunteers.
PartⅢ:Erythroeyte membrane phytosterol concentrations were determined by HPLC.The changes in shape and osmotic fragility in vitro of erythrocytes in sitosterol enriched plasma were studied.
Result
PartⅠ:Plasma concentrations of sitosterol,stigmasterol and cholestanol were markedly elevated in the affected patients.Their parents and other two family members showed slight elevation in plasma sitosterol and cholestanol levels compared with normal subjects,but their stigmasterol levels were normal.
PartⅡ:The affected patients had obviously large platelets and abnormal erythrocytes of various shapes,such as spherocytes,stomatocytes and target cells on the blood smear.Meanwhile,the erythrocytic osmotic fragility was highly increased.Their bleeding time was prolonged;their platelets had a low agglutination in response to ristocetin.They had increased plasma sitosterol,stigmasterol and cholestanol levels,but maintained normal cholesterol levels.Sequence analysis of ABCG5 and ABCG8 genes revealed a C to T transition at nucleotide 18802 resulting in a nonsense mutation in ABCG5 exon 1,Gln22X.The affected patients were homozygous whereas their parents and other two family members were heterozygous for this defect.Allele-specific restriction enzyme analysis using Bfa I did not detect this mutation in 70 healthy individuals.
PartⅢ:Three affected patients had increased erythrocyte membrane sitosterol levels.After erythrocytes were incubated with sitosterol,the shape changes of them were abnormal.Spherocytes,stomatocytes and target cells were easily observed on the blood smear.The osmotic fragility of sitosterol-enriched erythrocytes in vitro is increased compared to that of control cells
Conclusion
1.This method of the quantitative analysis of serum phytosterols by HPLC was found to be simple,quick and sensitive,to provide the referenced foundation for the biochemical diagnosis of phytosterolaemia.2.The blood cells could be a "target" in the toxic effect of plasma phytosterols in some patients,and the coexisting hematological abnormalities might represent a specific phenotype of sitosterolemia,which should be included in the differential diagnosis of inherited hemolytic anemia and(or) macrothrombocytopenia.A novel nonsense mutation Gln22X in ABCG5 gene reported in this study could be useful to investigate the molecular basis of sitosterolemia with erythrocyte and platelet abnormalities.This mutation is a novel mutation of phytosterolaemia,which,to our knowledge,has not been described before.3.The patients of phytosterolaemia had not only increased plasma phytosterol levels,but also increased erythrocyte membrane phytosterol levels.The increased plasma phytosterol levels had obvious influence on morphology and osmotic fragility of erythrocytes.
目的巨大血小板减少与溶血性贫血共存在血液病中十分罕见,而且人们对其认识不清。一些血液病表现为溶血性贫血伴血小板减少,如Evan's综合征、血栓性血小板减少性紫癜等,但它们的血小板体积不大。1969年由Ducrou等提出的地中海口形红细胞增多症/地中海巨大血小板减少症,临床上表现为口形红细胞增多性溶血性贫血和巨大血小板,但仅见于澳大利亚的Adelaide地区,未见于其它地中海地区,其病因和发病机制不清。1974年Bhaltacharyya等首次报道了植物固醇血症(又称β-谷固醇血症),它是一种罕见的常染色体隐性遗传性脂质代谢性疾病。特征是植物固醇特别是谷固醇在血液和组织中积聚,从而引起黄色瘤,早发性冠心病、动脉硬化、关节炎等。2005年Rees等首次报道了表现为口形红细胞增多和巨大血小板的植物固醇血症。最近,我们发现了来自江苏盐城的一个家庭的3个孩子自幼表现为溶血性贫血和巨大血小板减少,与地中海巨大血小板减少症相似,但随着年龄的增长逐渐出现皮肤的黄色瘤。为了了解这种血液学异常与植物固醇之间的关系,为了阐明此类疾病发生的分子机制以及将此类疾病与其它巨大血小板病区别开来,我们对此家系的临床、生物化学和分子生物学特征进行了研究。
方法第1部分建立特异精确的血浆植物固醇测定方法,以便植物固醇血症的诊断。制备谷固醇、豆固醇和二氢胆固醇标准溶液及收集患者、他们父母和10名正常人非抗凝禁食血2ml。100μl血清或标准溶液用1mol/L氢氧化钾乙醇溶液皂化,正己烷溶液提取,苯甲酰氯溶液衍生。衍生物再用正己烷溶液提取,然后在氮气流下挥发蒸干。非挥发物用100μl四氢呋喃:乙腈(1:1)溶解液溶解后,取10μl注入高效液相色谱(HPLC)进行测定。HPLC仪为美国Agilent1100系统,层析柱为Diamonsil C_(18),流动相为乙腈和异丙醇(75:25,v/v),流速为1ml/min。在235nm的波长下测定紫外吸收值。第2部分分析一个植物固醇血症家系的临床特征。光学显微镜观察红细胞和血小板形态。比浊法测定血小板聚集。流式细胞术检测血小板膜糖蛋白(GP)。PCR法扩增ABCG5和ABCG8基因的所有外显子和侧翼序列,DNA测序确定基因异常,限制性内切酶(BfaⅠ)分析该家系及70名正常人相应序列的PCR产物。第3部分用HPLC法检测3名患者、他们父母和6例正常人红细胞膜的固醇含量。将谷固醇与红细胞在体外进行孵育,观察正常人红细胞形态变化并检测其渗透脆性。
结果第1部分植物固醇血症患者血浆谷甾醇和豆甾醇浓度明显高于正常人均值。他们父母的谷固醇和二氢胆固醇浓度比正常人均值轻度增高,而豆固醇未见增高。第2部分3名患者临床上主要表现巨大血小板和红细胞形态异常,如球形、口形红细胞和靶形细胞。红细胞渗透脆行增加。出血时间延长、对瑞斯托霉素诱导聚集反应降低。他们血浆谷固醇、豆固醇和二氢胆固醇浓度明显增高而总胆固醇浓度正常。发现在ABCG5基因外显子1中18802位碱基发生C→T突变,导致22位的谷氨酰胺(Q)变为终止密码子。3名患者均为纯合子,其父母及两个亲属为杂合子。对ABCG8基因测序未见异常。限制性内酶BfaⅠ分析70名正常人相应序列的PCR产物未发现相同的基因突变。第3部分3名患者红细胞膜的谷固醇、豆固醇和二氢胆固醇浓度明显增高。谷固醇与红细胞孵育后,红细胞异形明显,可见口形、球形红细胞和靶形细胞。谷固醇组红细胞渗透脆性较对照组升高。
结论1.本研究采用改良的HPLC法对血浆植物固醇进行定量检测,该法具有简便快速,灵敏度高,需血样品量小及分离效果好等优点,为植物固醇血症的诊断提供了一种切实可行的检测方法。2.血细胞是血浆植物固醇毒性作用的一个靶子;显著增高的血浆植物固醇导致了红细胞和血小板的异常;红细胞和血小板的异常是植物固醇血症的一种特殊的表型;伴有巨大血小板和(或)难以解释的溶血性贫血的患者需与植物固醇血症鉴别。3.ABCG5基因外显子1上的一个新的无义突变构成了伴有红细胞和血小板异常的植物固醇血症的分子基础。此突变是国际尚未报道的一个新的突变。4.植物固醇血症患者不仅血浆植物固醇含量增加,而且红细胞膜上的植物固醇含量也增加:血浆植物固醇含量的增加对红细胞形态和渗透脆性有明显的影响。
Giant platelet disorders are a heterogeneous group of diseases with thrombocytopenia,large platelets and variable hemorrhagic phenomena,which are from either primary platelet disorders or a specific phenotype of other conditions.With the development of laboratory technology,some novel platelet disorders are constantly discovered.However,to date there are a lot of cases which are not classified and identified.Recently,we found a rare case with macrothrombocytopenia,abnormal erythrocyte shape,hemolysis and increased plasma levels of phytosterols.Although rare, the further research on particular disorders with giant platelets will help clinicians correctly understand,diagnose and treat them.This work may provide a valuable reference for clinicians.
Objective
The combination of macrothrombocytopenia and hemolysis is an unusually and poorly understood hematological condition.Some of hematological diseases present with hemolysis and thrombocytopenia,such as Evan's syndrome,thrombotic thrombocytopenic purpura.In none of these conditions were the platelets large. Mediterranean stomatocytosis/macrothrombocytopenia was first described in individuals of Mediterranean origin in Adelaide,Australia by Ducrou in 1969.No reports arose from any other Australian centre,nor from any Mediterranean country. The exact nature of this condition that combines stomatocytic hemolysis with the presence of very large platelets has never been elucidated.Phytosterolaemia is a rare autosomal recessive disorder,first described by Bhattacharyya in 1974,characterized by hyperabsorption of plant sterols from the intestine and inability to excrete these sterols into the bile.As a consequence,affected individuals show very high levels of plant sterols.The patients suffer from tendon and tuberous xanthomas and premature atherosclerosis and coronary artery disease.Rees first reported phytosterolaemia associated stomatocytic hemolysis and macrothrombocytopenia in 2005.Recently,we found a family with phytosterolaemia from Jiangsu province,China,all children of which showed hemolysis with very large platelets,conforming to the description of Mediterranean macrothrombocytopenia.However,since the age of over10 years they had noticed enlarging tendon and tuberous xanthomas that began on the both elbows, and then in hips.To analyze the relationship between hematological abnormalities and phytosterolaemia,elucidate the molecular mechanisms of this disorder and distinguish it from other syndromes associated with giant platelets,in this study,we characterized the clinical,biochemical and molecular genetic features of a Chinese family with phytosterolaemia that mainly manifested hematological abnormalities.
Methods
PartⅠ:A simple,rapid and accurate method to separate and quantify serum sterols was performed by high performance liquid chromatography(HPLC).No coagulant fasting blood samples were collected from the affected patients,their parents,other two family members and 10 normal volunteers.Briefly,100μl of serum,or 10 mg/dl stigmasterol,2.5 mg/dl cholestanol and 1.5 mg/dl sitosterol standard was placed respectively in a screw-capped test-tube,and then 1ml of 1M ethanolic potassium hydroxide was added.After vigorous stirring,the saponified mixture was allowed to stand for 1h at 80℃,and then 1ml of water was added.The unsaponifiable material was extracted with two-2ml portions of hexane.The extracts were evaporated under a stream of nitrogen.The sterols in the extracts were converted into benzoate derivatives with benzoyl chloride,and then re-extracted with hexane.The hexane layer was again evaporated under nitrogen.Finally,the residue was dissolved in 0.1 ml of acetonitrile-tetrahydrofuran(1:1,v/v),and 10μl were injected into the HPLC system. The instrument was an Agilent 1100 HPLC system,equipped with a Diamonsil C_(18) column which was maintained at 30℃.The solvent was acetonitrile-isopropylalcohol (75:25,v/v) at a flow-rate of 1 ml/min.Steryl benzoates were detected by their absorbance at 235 nm.
PartⅡ:The clinical features of the affected patients in this family were analyzed. Erythrocyte and platelet morphology was observed under light microscope.Platelet aggregation was measured turbidometrically.Platelet glycoproteins(GPs) were analyzed using flow cytometry.Their plasma sterol levels were measured by HPLC method.ABCG5 and ABCG8 genes sequencing was searched for the mutation. Restriction endonuclease analysis was used for the PCR products of exon 1 of ABCG5 and its flanking regions of the family members and 70 healthy volunteers.
PartⅢ:Erythroeyte membrane phytosterol concentrations were determined by HPLC.The changes in shape and osmotic fragility in vitro of erythrocytes in sitosterol enriched plasma were studied.
Result
PartⅠ:Plasma concentrations of sitosterol,stigmasterol and cholestanol were markedly elevated in the affected patients.Their parents and other two family members showed slight elevation in plasma sitosterol and cholestanol levels compared with normal subjects,but their stigmasterol levels were normal.
PartⅡ:The affected patients had obviously large platelets and abnormal erythrocytes of various shapes,such as spherocytes,stomatocytes and target cells on the blood smear.Meanwhile,the erythrocytic osmotic fragility was highly increased.Their bleeding time was prolonged;their platelets had a low agglutination in response to ristocetin.They had increased plasma sitosterol,stigmasterol and cholestanol levels,but maintained normal cholesterol levels.Sequence analysis of ABCG5 and ABCG8 genes revealed a C to T transition at nucleotide 18802 resulting in a nonsense mutation in ABCG5 exon 1,Gln22X.The affected patients were homozygous whereas their parents and other two family members were heterozygous for this defect.Allele-specific restriction enzyme analysis using Bfa I did not detect this mutation in 70 healthy individuals.
PartⅢ:Three affected patients had increased erythrocyte membrane sitosterol levels.After erythrocytes were incubated with sitosterol,the shape changes of them were abnormal.Spherocytes,stomatocytes and target cells were easily observed on the blood smear.The osmotic fragility of sitosterol-enriched erythrocytes in vitro is increased compared to that of control cells
Conclusion
1.This method of the quantitative analysis of serum phytosterols by HPLC was found to be simple,quick and sensitive,to provide the referenced foundation for the biochemical diagnosis of phytosterolaemia.2.The blood cells could be a "target" in the toxic effect of plasma phytosterols in some patients,and the coexisting hematological abnormalities might represent a specific phenotype of sitosterolemia,which should be included in the differential diagnosis of inherited hemolytic anemia and(or) macrothrombocytopenia.A novel nonsense mutation Gln22X in ABCG5 gene reported in this study could be useful to investigate the molecular basis of sitosterolemia with erythrocyte and platelet abnormalities.This mutation is a novel mutation of phytosterolaemia,which,to our knowledge,has not been described before.3.The patients of phytosterolaemia had not only increased plasma phytosterol levels,but also increased erythrocyte membrane phytosterol levels.The increased plasma phytosterol levels had obvious influence on morphology and osmotic fragility of erythrocytes.
引文
1.Bhattacharyya AK,Connor WE.Beta-sitosterolemia and xanthomatosis.A newly described lipid storage disease in two sisters.J Clin Invest,1974,53:1033-1043.
2.Salen G,Shefer S,Nguyen L,et al.Sitosterolemia.J Lipid Res,1992,33:945-955.
3.Miettinen TA.Phytosterolaemia,xanthomatosis and premature atherosclerotic arterial disease:a case with high plant sterol absorption,impaired sterol elimination and low cholesterol synthesis.Eur J Clin Invest,1980,10:27-35.
4.Hidaka H,Nakamura T,Aoki T,et al.Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis.J Lipid Res,1990,31:881-888.
5.Hidaka H,Yasuda H,Kobayashi M,et al.Familial spinal xanthomatosis with sitosterolemia.Intern Med,1992,31:1038-1042.
6.Shefer S,Salen G,Bullock J,et al.The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-methylglutaryl-coenzyme.A reductase and cholesterol 7alpha-hydroxylase in the rat and sitosterolemic homozygotes.Hepatology,1994,20:213-219.
7.Rees DC,Iolascon A,Carella M,et al.Stomatocytic haemolysis and macrothrombocytopenia(Mediterranean stomatocytosis/macrothrombocytopenia)is the haematological presentation of phytosterolaemia.Br J Haematol,2005,130:297-309.
8.Hicks K,Moreau R.Phytosterols and phytostanols:functional food cholesterol busters.Food Technology,2001,55:63-67.
9.Morton GM,Lee SM,Buss DH,et al.Intakes and major dietary sources of cholesterol and phytosterols in the British diet.J Human Nutr Dietet,1995,8:429-440.
10.Schothorst RC,JekelAA.Oral sterol intake in the Netherlands:evaluation of the results obtained by GC analysis of duplicate 24-h diet samples collected 1994. Food Chem, 1999,64:561-566.
11. Patel SB, SalmG, Hidaka H, et al. Mapping a gene involved inregulating dietary cholesterol absorption. The sitwterolemia locus is found at chromosome 2p21. J Clin Invest, 1998,102: 1041-1044.
12. Lee MH, Lu K, Hazard 5, et al. Identification of a gene, ABCG5, important in the regulatioor of dietary cholesterol absorption. Nat Genet, 2001,27: 79-83.
13. Lu k, Lee. MH, Hasard S, et al. Two genes that map to the STSLlocus cause sitosterolernis:genomic structure and spectrum of murations involving sterolin-1 and steroOn-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet, 2001,69:278-290.
14. Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science, 2000, 290:1771-1775.
15. Klein I, Sarkadi B, Varadi A. An inventory of the human ABC proteins. Biochim. Biophys Acta, 1999; 1461:237-262.
16. Schmitz G, Langmann T, Heimerl S. Role of ABCG1 and other ABCG family members in lipid metabolism. J Lipid Res 2001, 42 (10) : 1513-1520.
17. Togo M, Toda T, Nguyen LA, et al. Genetic analysis of phytosterolaemia. J Inherit MetabDis, 2001,24:43-50.
18. Graf GA, Lf WP, Gerard RD, et al, Coexpression of ATP binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest, 2002,110:659-669.
19. Repa JJ, Berge KE, Pomajzl C, et al. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta . J Biol Chem, 2002,277: 18793—18800.
20. Hubacek JA, Berge KE, Cohen JC, et al. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat, 2001, 18359-18360.
21. Heimerl S, Langmann T, Moehle C, et al. Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia. Hum Mutat, 2002, 20:151.
22. Lam CW, Cheng AW, Ton SF, et al. Novel donor splice site mutation of ABCG5 gene in sitosterolemia. Mol Genet Metab, 2002,75178-75180.
23. Mymin D, Wang J, Frohlich J, et al. Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8. Circulation, 2003,107:791.
24. Yu L, Li-Hawkins JR, Hammer RE, et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol. J Clin Invest, 2002,110:671-680.
25. Yu L, Hammer RE, Li-Hawkins JR, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci. USA, 2002,99:16237-16242.
26. Ratnayake WMN, L' Abbe MR, Mueller R, et al. Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr, 2000,130:1166-1178.
1.Bhattacharyya AK,Connor WE.β-sitosterolemia and xanthomatosis-a newly described lipid storage disease in two sisters.J Clin Invest,1974,53:1033-1043.
2.Mietinnen,TA.Phytosterolaemia,xanthomatosis and premature coronary atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis. Eur J Clin Invest, 1980, 10: 27-35.
3. Salen G, Shefer S, Nguyen L, et al. Sitosterolemia. J Lipid Res, 1992,33: 945-955.
4. Lutjohann D, Bjorkhem I, Beil UF, et al. Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment. J Lipid Res, 1995,36:1763-1773.
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6. Salen G., Shore V, Tint GS, et al. Increased sitosterol absorption, decreased removal, and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis. J Lipid Res, 1989,30:1319-1330.
7. Salen G., Tint GS, Sh(?)fer S, et al. Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia. Arterioscler Thromb, 1992,12: 563-568.
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1 Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science, 2000, 290:1771-1775.
2 Lam CW, Cheng AW, Tong SF, et al. Novel donor splice site mutation of ABCG5 gene in sitosterolemia. Mol Genet Metab, 2002,752:178-180.
3 Wang C, Lin HJ, Chan TK, et al. A unique patient with coexisting cerebrotendinous xanthomatosis and beta-sitosterolemia. Am J Med, 1981,71:313-319.
4 Rees DC, Iolascon A, Carella M, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol, 2005, 130:297-309.
5 Wang J, Joy T, Mymin D, et al. Phenotypic heterogeneity of sitosterolemia. J Lipid Res, 2004,45:2361-2367.
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7 Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. Journal of Clinical Investigation, 1974, 53,1033-1043.
8 Salen G, Horak I, Rothkopf M, et al. Lethal atherosclerosis associated with abnormal plasma and tissue sterol composition in sitosterolemia with xanthomatosis. J Lipid Res, 1985,26:1126-1133.
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10 Ratnayake WM, L'Abbe MR, Mueller R, et al. Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr, 2000, 130:1166-1178.
11 Mietinnen, TA. Phytosterolaemia, xanthomatosis and premature coronary atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis. Eur J Clin Invest, 1980,10: 27-35.
12 Salen G, Shefer S, Nguyen L, et al. Sitosterolemia. J Lipid Res, 1992; 33: 945-955.
13 utjohann D, Bjorkhem I, Beil UF, et al. Sterol absorption and sterol balance in phytosterolemia evaluated by deuterium-labeled sterols: effect of sitostanol treatment. J Lipid Res, 1995,36:1763-1773.
14 Salen G., Shore V, Tint GS, et al. Increased sitosterol absorption, decreased removal, and expanded body pools compensate for reduced cholesterol synthesis in sitosterolemia with xanthomatosis. J Lipid Res, 1989,30:1319-1330.
15 Salen G., Tint GS, Shefer S, et al. Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia. Arterioscler Thromb, 1992,12: 563-568.
16 Schmitz G, Langmann T, Heimerl S. Role of ABCG1 and other ABCG family members in lipid metabolism. J Lipid Res, 2001, 42 (10) :1513-1520.
17 Graf GA, Lf WP, Gerard RD, et al. Coexpression of ATP binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest, 2002, 110(5): 659-669.
18 Lu K, Lee MH, Hazard S, et al. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet, 2001,69: 278-290.
19 Lee MH, Lu K, Hazard S, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet, 2001,2779-2783.
20 Hubacek JA, Berge KE, Cohen JC, et al. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat, 2001, 18359-18360.
21 Heimerl S, Langmann T, Moehle C, et al. Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia. Hum Mutat, 2002, 20:151.
22 Mymin D, Wang J, Frohlich J, et al. Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8. Circulation, 2003,107:791.
23 Pandit B, Ahn GS, Hazard SE, et al. A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans. BMC Med Genet, 2006,28(7): 13.
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2.Salen G,Shefer S,Nguyen L,et al.Sitosterolemia.J Lipid Res,1992,33:945-955.
3.Miettinen TA.Phytosterolaemia,xanthomatosis and premature atherosclerotic arterial disease:a case with high plant sterol absorption,impaired sterol elimination and low cholesterol synthesis.Eur J Clin Invest,1980,10:27-35.
4.Hidaka H,Nakamura T,Aoki T,et al.Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis.J Lipid Res,1990,31:881-888.
5.Hidaka H,Yasuda H,Kobayashi M,et al.Familial spinal xanthomatosis with sitosterolemia.Intern Med,1992,31:1038-1042.
6.Shefer S,Salen G,Bullock J,et al.The effect of increased hepatic sitosterol on the regulation of 3-hydroxy-3-methylglutaryl-coenzyme.A reductase and cholesterol 7alpha-hydroxylase in the rat and sitosterolemic homozygotes.Hepatology,1994,20:213-219.
7.Rees DC,Iolascon A,Carella M,et al.Stomatocytic haemolysis and macrothrombocytopenia(Mediterranean stomatocytosis/macrothrombocytopenia)is the haematological presentation of phytosterolaemia.Br J Haematol,2005,130:297-309.
8.Hicks K,Moreau R.Phytosterols and phytostanols:functional food cholesterol busters.Food Technology,2001,55:63-67.
9.Morton GM,Lee SM,Buss DH,et al.Intakes and major dietary sources of cholesterol and phytosterols in the British diet.J Human Nutr Dietet,1995,8:429-440.
10.Schothorst RC,JekelAA.Oral sterol intake in the Netherlands:evaluation of the results obtained by GC analysis of duplicate 24-h diet samples collected 1994. Food Chem, 1999,64:561-566.
11. Patel SB, SalmG, Hidaka H, et al. Mapping a gene involved inregulating dietary cholesterol absorption. The sitwterolemia locus is found at chromosome 2p21. J Clin Invest, 1998,102: 1041-1044.
12. Lee MH, Lu K, Hazard 5, et al. Identification of a gene, ABCG5, important in the regulatioor of dietary cholesterol absorption. Nat Genet, 2001,27: 79-83.
13. Lu k, Lee. MH, Hasard S, et al. Two genes that map to the STSLlocus cause sitosterolernis:genomic structure and spectrum of murations involving sterolin-1 and steroOn-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet, 2001,69:278-290.
14. Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science, 2000, 290:1771-1775.
15. Klein I, Sarkadi B, Varadi A. An inventory of the human ABC proteins. Biochim. Biophys Acta, 1999; 1461:237-262.
16. Schmitz G, Langmann T, Heimerl S. Role of ABCG1 and other ABCG family members in lipid metabolism. J Lipid Res 2001, 42 (10) : 1513-1520.
17. Togo M, Toda T, Nguyen LA, et al. Genetic analysis of phytosterolaemia. J Inherit MetabDis, 2001,24:43-50.
18. Graf GA, Lf WP, Gerard RD, et al, Coexpression of ATP binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest, 2002,110:659-669.
19. Repa JJ, Berge KE, Pomajzl C, et al. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta . J Biol Chem, 2002,277: 18793—18800.
20. Hubacek JA, Berge KE, Cohen JC, et al. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat, 2001, 18359-18360.
21. Heimerl S, Langmann T, Moehle C, et al. Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia. Hum Mutat, 2002, 20:151.
22. Lam CW, Cheng AW, Ton SF, et al. Novel donor splice site mutation of ABCG5 gene in sitosterolemia. Mol Genet Metab, 2002,75178-75180.
23. Mymin D, Wang J, Frohlich J, et al. Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8. Circulation, 2003,107:791.
24. Yu L, Li-Hawkins JR, Hammer RE, et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol. J Clin Invest, 2002,110:671-680.
25. Yu L, Hammer RE, Li-Hawkins JR, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci. USA, 2002,99:16237-16242.
26. Ratnayake WMN, L' Abbe MR, Mueller R, et al. Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr, 2000,130:1166-1178.
1.Bhattacharyya AK,Connor WE.β-sitosterolemia and xanthomatosis-a newly described lipid storage disease in two sisters.J Clin Invest,1974,53:1033-1043.
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