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研究生:張瑞宏
研究生(外文):Chang, Jui-Hung
論文名稱:人類遺傳疾病 第一部份:第二型黏多醣儲積症IDS基因的分子遺傳研究第二部份:家族性高膽固醇血症LDL受體基因突變的記述 
論文名稱(外文):Human Genetic Diseases:Part I: Molecular and genetic studies of the IDS gene associated with mucopolysaccharidosis type II. Part II: Characterization of LDL Receptor Gene Mutations in Familial Hypercholesterolemia.
指導教授:李桂楨李桂楨引用關係
學位類別:博士
校院名稱:國立臺灣師範大學
系所名稱:生物學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
畢業學年度:93
語文別:中文
論文頁數:88
中文關鍵詞:黏多醣儲積症溶小體低密度脂蛋白受體突變外毒素
外文關鍵詞:mucopolysaccharidoseslysosomeiduronate-2-sulfataseLDL receptorpseudomonas exotoxin Amutation
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第一部份:第二型黏多醣儲積症IDS基因的分子遺傳研究

摘 要

第二黏多醣儲積症(又稱Hunter syndrome)為X染色體隱性遺傳性疾病,其起因為缺乏分解heparan sulphate及dermatan sulphate的溶小體水解酵素iduronate-2-sulfatase (IDS)。全世界有接近三百種和MPS II相關的突變被報導。本研究利用單股核酸構形多型性及DNA定序等技術,對臺灣地區10位來自不同家庭且無血緣關係的MPS II患者進行分子致因研究,結果發現5種新穎的和5種已報導過的突變。合計先前臺灣14位MPS II患者的IDS基因變異分析所發現的10種突變,於24位的臺灣MPS II患者共發現20種突變,顯示IDS基因突變的高度異質性變化。R468Q和R468W突變分別發現於3位無血緣關係的患者,其發生率共佔25.0%。利用IDS基因鄰近的DXS1123、DXS1113二核重複多型性標記,建構突變基因的單套型,結果發現無血緣關係的R468Q突變為不同的起源,但無血緣關係的R468W突變則可能具相同的起源。患者1150的R468Q突變及患者710的I485R突變發生於精蟲形成的減數分裂。白血球酵素活性檢測顯示,正常人族群及女性MPS II突變基因攜帶者的IDS酵素活性範圍分別為19.2 ~ 70.6、8.4 ~ 26.6 nmol/h/mg cell protein,分佈範圍雖然有顯著差異,且女性攜帶者的平均酵素活性值亦低於正常人平均值的一半,但因為兩樣品群活性範圍的小部分重疊,故單獨檢測白血球酵素活性的數值,並不能用來判斷是否為突變基因攜帶者。此外本研究亦對所發現的17種胺基酸置換、缺失及終止密碼突變做進一步記述。突變的IDS cDNA轉移入COS-7細胞後,各突變的cDNA所表現的IDS活性,僅為野生型cDNA的0% ~ 3.9%,顯示突變的有害;但僅231del6突變造成mRNA的不穩定性(降低57%)。西方吸漬分析及共軛焦顯微鏡分析顯示,所檢測的11種單一胺基酸置換突變,僅K347E突變酵素成熟蛋白的大小及生成量與野生型酵素相似,其餘10種點突變前軀蛋白表面上正常,但成熟蛋白量降低或不具,顯示突變蛋白的正常成熟但無法正常運送至溶小體。所檢測的6個缺失、終止密碼突變中,1055del12和E521X的成熟不正常,共軛焦顯微鏡分析顯示截短的W267X和1184delG滯留在早期的vacuolar隔間。231del6和1421delAG則未看到表現的IDS蛋白,顯示突變IDS蛋白的不穩定性及被分解。在增進IDS重組蛋白在酵素替換治療應用的研究上,PEIa銜接的IDS較易被COS-7細胞分泌出去,被細胞內噬後亦生成有活性的酵素,但銜接的PEIa並沒有預期的
結合LRP的功能。黏多醣儲積症的分子遺傳學研究,可清楚的確認患者的分子致因並提供出生前及家族檢測。進一步的突變記述來釐清突變對IDS酵素活性及成熟的影響,可將此疾病的症狀和基因型相關聯,提供臨床上預後及治療方法的評估。

第二部份:家族性高膽固醇血症LDL受體基因突變的記述

摘要

家族性高膽固醇血症(familial hypercholesterolemia,簡稱FH)為一體染色體顯性遺傳疾病,患者因低密度脂蛋白(LDL)受體基因突變而導致血漿中LDL膽固醇值過高,易發展出早發性的冠狀心臟病。至今有超過840種分散在LDL受體基因上的缺失、插入、點突變、裁接突變被報導。先前本實驗室檢測了170位膽固醇濃度大於240 mg/dl的高脂血症患者LDL受體基因,於患者中發現10種可能和疾病相關的變異,包括兩種缺失變異(Del e3-5 和Del e6-8)及八種點變異(W-18X、D69N、R94H、E207K、C308Y、I402T、A410T、A696G)。本研究延續上述發現,對檢測到的變異作進一步的記敘。結果發現A696G cDNA質體轉移細胞LDL受體的表現量和活性與野生型受體相近。含D69N突變的cDNA質體表現時出現異常的中間型蛋白。含R94H、E207K、C308Y、I402T及A410T突變的LDL受體活性為野生型的20 ~ 64%。相對的,Del e3-5及Del e6-8突變的LDL受體活性僅為野生型的0 ~ 13%。D69N、R94H、E207K、C308Y及I402T等突變受體大部分停留在內質網,A410T及Del e6-8突變受體則停留在endosome/lysosome。此LDL受體的分生研究能清楚的確定病人的高血脂原因,可應用於出生前、家族分析及提供臨床上治療的評估。
Part I: Molecular and genetic studies of the IDS gene associated with
mucopolysaccharidosis type II

Abstract

Hunter syndrome (mucopolysaccharidosis type II) is an X-linked recessive lysosomal storage disease caused by a defect of the iduronate-2-sulfatase (IDS) gene. Nearly 300 different mutations underlying mucopolysaccharidosis type II (MPS II) have been identified worldwide. To investigate the molecular lesions underlying Taiwanese MPS II, 10 probands and families were identified and screened for iduronate-2-sulfatase (IDS) mutation by single strand conformation polymorphism and DNA sequencing. Five novel and five previously reported mutations were found. Together with the previously reported 10 mutations in 14 probands and families, a total of 20 mutations were identified in 24 Taiwanese MPS II patients, supporting the mutational heterogeneity for MPS II. The identified R468Q and R468W account for 25.0% mutations found in our patients. Haplotype analysis using flanking DXS1113 and DXS1123 revealed that the unrelated R468Q alleles are independent origin whereas the unrelated R468W alleles are probably of the same origin. The R468Q mutation in patient 1150 and I485R mutation in patient 710 occurred de novo in male meioses. Leukocyte IDS measurement revealed significantly different range of IDS activity in normal controls and MPS II carriers (19.2 ~ 70.6 vs.8.4 ~ 26.6 nmol/h/mg cell protein). The mean leukocyte IDS activity in female carriers was less than a half of the normal level. However, due to a small overlapping range of normal and carriers, the level of enzyme activity can not be used alone for carrier detection. In addition, a total of 17 identified missense, small deletion, and nonsense mutations were further characterized by transient expression studies. Transfection of COS-7 cells by the mutated cDNA did not yield active enzyme, demonstrating the deleterious nature of the mutations. A 57% decrease in IDS mRNA level was seen with 231del6 mutation. Among the 11 missense mutations examined, K347E substitution showed apparent normal maturation and targeting on immunoblot and confocal fluorescence microscopy examination. The rest 10 missense mutations showed apparent normal precursor with little or reduced mature forms, indicating normal maturation but incorrect targeting of the mutant enzymes. Among the 6 deletion and nonsense mutations examined, 1055del12 and E521X showed abnormal maturation. The staining pattern of truncated W267X and 1184delG proteins suggested retention within early vacuolar compartments. The mutated 231del6 and 1421delAG proteins were unstable and largely degraded. To improve the uptake of the recombinant enzyme for enzyme replacement therapy, PEIa-fused IDS showed increased secretion profiles, leading to increased uptake compared with the wild-type enzyme. However, the expected LRP-mediated uptake was not observed. Molecular and genetic studies of the IDS gene will clearly identify the patient's cause and allow antenatal and family studies. The further characterization of gene mutations may delineate their functional consequence on IDS activity and processing and may enable future studies of genotype-phenotype correlation to estimate prognosis and to lead to possible therapeutic intervention.

Part II: Characterization of LDL Receptor Gene Mutations in
Familial Hypercholesterolemia

Abstract


Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased levels of plasma LDL cholesterol, which cause cholesterol deposition in tissues in the form of tendon xanthomas and atheroma, leading in turn to premature arteriosclerosis and coronary heart disease. FH is caused by mutations in the LDL receptor gene resulting in defective clearance of plasma LDL. To date, more than 840 mutations including gross deletions, minor deletions, insertions, point mutations, and splice-site mutations scattered over the LDL receptor gene have been reported. Previously DNA screening for LDL receptor mutations was performed in 170 unrelated hyperlipidemic Chinese patients and two clinically diagnosed familial hypercholesterolemia patients. Two deletions (Del e3-5 and Del e6-8) and eight point mutations (W-18X, D69N, R94H, E207K, C308Y, I402T, A410T, and A696G) were identified. The effects of the identified mutations on LDL receptor function were characterized in the present study. The LDL receptor level and activity were close to those of wild type in A696G transfected cells. A novel intermediate protein and reduction of LDL receptor activity were seen in D69N transfected cells. For R94H, E207K, C308Y, I402T and A410T mutations, only 20~64% of normal receptor activities were seen. Conversely, Del e3-5 and Del e6-8 lead to defective proteins with 0~13% activity. Most of the mutant receptors were localized intracellularly, with a staining pattern resembling that of ER (D69N, R94H, E207K, C308Y and I402T) or endosome/lysosome (A410T and Del e6-8). Molecular analysis of the LDL receptor gene will clearly identify the cause of the patient's hyperlipidemia and allow appropriate early treatment as well as antenatal and family studies.
Index…………………………………………………………………………………....I
LIST of ABBREVIATIONS.........................................................................................XIII


Part I: Molecular and genetic studies of the IDS gene associated with
mucopolysaccharidosis type II

List of figures and tables………………………………………………………………V
Abstract (Chinese) ……………………………………………………………………VII
Abstract …………………………………………………………………………..….IX
Introduction ………………………………………………..………………….……….1
Proteoglycan and glycosaminoglycan……………………………………………...1
Glycosaminoglycan degradation…………………………………………………...1
Cellular biology of lysosomal enzyme……………………………………………..2
Lysosomal storage diseases……………………………………………………..….3
Mucopolysaccharidoses (MPS)…………………………………………………….4
Mucopolysaccharidosis type II (MPS II)..................................................................5
Diagnosis of MPS II………………………………………………………………..5
Iduronate-2-sulfatase (IDS) gene and mRNA………………………………………….6
IDS proteins………………………………………………………………………...…6
IDS mutations………………………………………………………………………....7
Treatment of MPS…………………………………………………………….……8
(1) Enzyme replacement therapy………………………………….……………….8
(2) Cell and tissue transplantation…………………………………........................9
(3) Gene therapy…………………………………………………………………...9
Pseudomonas exotoxin A (PE) and lipoprotein receptor-related protein (LRP)…..…..10
Aims…………………………………………………………………………………..11
Materials and Methods………………………………………………………………..12
Patients………………………………………………………………………….…12
I
Mutation analysis………………………………………………………………….12
Measurement of leukocyte IDS activity…………………………………………..13
Haplotype Analysis………………………………………………………………..13
cDNA constructs…………………………………………………………………..13
IDS antibody preparation………………………………………………………….14
Expression studies…………………………………………………………………14
Immunofluorescence and microscopy……………………………………………..15
Construction of PEIa-IDS and IDS-PEIa recombinant proteins……..…………...…..15
PEIa-IDS and IDS-PEIa uptake by LRP……………………………..……………….16
Results……………………………………………………………...…………………17
Identification of mutations…………………………..………….…………………17
IDS activity measurement…………………………………………………...…….17
Haplotype analysis on the mutant allele…………………………..………………17
Expression of IDS cDNA mutants……………………………………………..….18
Expression and uptake of PEIa-IDS and IDS-PEIa recombinant proteins……..…….19
Discussion……………………………………………………………….....................21
IDS activity in MPS II patients and female carriers……………………………....21
Mutation identification and characterization…………………………………..….21
Haplotype analysis on the mutant allele……………………………………..……23
Secretion and uptake of PEIa-IDS and IDS-PEIa………………………...………..…24
Conclusions……………………………………………………………………….25
References………………………………………………………………....................26


Part II: Characterization of LDL Receptor Gene Mutations in
Familial Hypercholesterolemia

List of figures and tables……………………………………………………………….VI
Abstract (Chinese)……………………………………………………………….….….XI
Abstract……………………………………………………………….………….…….XII
II
Introduction ……………………………………………………………….……….…...59
Lipoproteins………………………………………………………………….………59
Cholesterol metabolism………………………………………………...……………59
Hyperlipidemia and atherosclerosis………………………….……………………….60
Familial defective apolipoprotein B-100 (FDB)……………………...……………..61
Familial hypercholesterolemia (FH)……………………………………………...….61
The LDL receptor gene: relation of exons to protein domains…...………………….61
The LDL receptor pathway…………………………………………………..…..…..63
Regulation of LDL receptor synthesis……………………………………………….63
LDL receptor mutations…………………………………………………………...…63
Aims…………………………………………………………………………………..….65
Materials and Methods…………………………………………………………….…..66
cDNA constructs………………………………………………………………….….66
COS-7 cells transfection…………………………………………………….…….…66
Reversed transcription-PCR……………………………………………………….…66
Western blot analysis……………………………………………………………...…67
Flow cytometric analysis………………………………………………………...…..67
Immunofluorescence and microscopy………………………………………….……68
Results……………………………………………………………………...………...….69
Expression of LDL receptor cDNA mutants…………………………………….….69
LDL receptor function………………………………………………………..….….69
Discussion……………………………………………………………………………..71
Mutation characterization…………………………………………………………….71
(1) D69N mutation.......................................................................................................71
(2) R94H mutation.......................................................................................................71
(3) E207K mutation.....................................................................................................72
(4) C308Y mutation.....................................................................................................72
(5) I402T and A410T mutations……………………..............................……………72
(6) A696G mutation………………………………………...………………………..73
(7) Del e3-5 and Del e6-8 deletions.............................................................................73
III
Conclusions...................................................................................................................73
References.........................................................................................................................74
References

Allured, V. S., Collier, R. J., Carroll, S. F. and McKay, D. B. (1986) Structure of exotoxin A of Pseudomonas aeruginosa at 3.0-Angstrom resolution. Proc Natl Acad Sci U S A 83(5):1320-4.

Bergstrom, S. K., Quinn, J. J., Greenstein, R. and Ascensao, J. (1994) Long-term follow-up of a patient transplanted for Hunter's disease type IIB: a case report and literature review. Bone Marrow Transplant 14(4):653-8.

Bielicki, J., Freeman, C., Clements, P. R. and Hopwood, J. J. (1990) Human liver iduronate-2-sulphatase. Purification, characterization and catalytic properties. Biochem J 271(1):75-86.

Bondeson, M. L., Malmgren, H., Dahl, N., Carlberg, B. M. and Pettersson, U. (1995) Presence of an IDS-related locus (IDS2) in Xq28 complicates the mutational analysis of Hunter syndrome. Eur J Hum Genet 3(4):219-27.

Bonuccelli, G., Di Natale, P., Corsolini, F., Villani, G. and Filocamo, M. (2001) The effect of four mutations on the expression of iduronate-2-sulfatase in Mucopolysaccharidosis type II. Biochim Biophys Acta 1537(3):233-8.

Braun, S. E., Aronovich, E. L., Anderson, R. A., Crotty, P. L., McIvor, R. S. and Whitley, C. B. (1993) Metabolic correction and cross-correction of mucopolysaccharidosis type II (Hunter syndrome) by retroviral-mediated gene transfer and expression of human iduronate-2-sulfatase. Proc Natl Acad Sci U S A 90(24):11830-4.

Braun, S. E., Pan, D., Aronovich, E. L., Jonsson, J. J., McIvor, R. S. and Whitley, C. B. (1996) Preclinical studies of lymphocyte gene therapy for mild Hunter syndrome (mucopolysaccharidosis type II). Hum Gene Ther 7(3):283-90.

Bu, G., Sun, Y., Schwartz, A. L. and Holtzman, D. M. (1998) Nerve growth factor induces rapid increases in functional cell surface low density lipoprotein receptor-related protein. J Biol Chem 273(21):13359-65.

Bunge, S., Steglich, C., Beck, M., Rosenkranz, W., Schwinger, E., Hopwood, J. J. and Gal, A. (1992) Mutation analysis of the iduronate-2-sulfatase gene in patients with mucopolysaccharidosis type II (Hunter syndrome). Hum Mol Genet 1(5):335-9.

Coppa, G. V., Gabrielli, O., Zampini, L., Jetzequel, A. M., Miniero, R., Busca, A., De Luca, T. and Di Natale, P. (1995) Bone marrow transplantation in Hunter syndrome. J Inherit Metab Dis 18(1):91-2.

Cooper, D. N. and Youssoufian, H. (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78(2):151-5.

Crotty, P. L., Braun, S. E., Anderson, R. A. and Whitley, C. B. (1992) Mutation R468W of the iduronate-2-sulfatase gene in mild Hunter syndrome (mucopolysaccharidosis type II) confirmed by in vitro mutagenesis and expression. Hum Mol Genet 1(9):755-7.

Cudry, S., Froissart, R., Bouton, O., Maire, I. and Bozon, D. (1999) The 2.1-, 5.4- and 5.7-kb transcripts of the IDS gene are generated by different polyadenylation signals. Biochim Biophys Acta 1447(1):35-42.

Cudry, S., Tigaud, I., Froissart, R., Bonnet, V., Maire, I. and Bozon, D. (2000) MPS II in females: molecular basis of two different cases. J Med Genet 37(10):E29.

Daniele, A., Faust, C. J., Herman, G. E., Di Natale, P. and Ballabio, A. (1993) Cloning and characterization of the cDNA for the murine iduronate sulfatase gene. Genomics 16(3):755-7.

Descamps, O., Bilheimer, D. and Herz, J. (1993) Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes. J Biol Chem 268(2):974-81.

Di Natale, P. and Daniele, A. (1985) Iduronate sulfatase from human placenta. Biochim Biophys Acta 839(3):258-61.

Di Natale, P., Di Domenico, C., Villani, G. R., Lombardo, A., Follenzi, A. and Naldini, L. (2002) In vitro gene therapy of mucopolysaccharidosis type I by lentiviral vectors. Eur J Biochem 269(11):2764-71.

Filocamo, M., Bonuccelli, G., Corsolini, F., Mazzotti, R., Cusano, R. and Gatti, R. (2001) Molecular analysis of 40 Italian patients with mucopolysaccharidosis type II: New mutations in the iduronate-2-sulfatase (IDS) gene. Hum Mutat 18(2):164-5.

Fitzgerald, D. J., Fryling, C. M., Zdanovsky, A., Saelinger, C. B., Kounnas, M., Strickland, D. K. and Leppla, S. (1994) Selection of Pseudomonas exotoxin-resistant cells with altered expression of alpha 2MR/LRP. Ann N Y Acad Sci 737:138-44.

Froissart, R., Millat, G., Mathieu, M., Bozon, D. and Maire, I. (1995) Processing of iduronate 2-sulphatase in human fibroblasts. Biochem J 309:425-30.

Froissart, R., Maire, I., Millat, G., Cudry, S., Birot, A. M., Bonnet, V., Bouton, O. and Bozon, D. (1998) Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients. Clin Genet 53(5):362-8.

Flomen, R. H., Green, E. P., Green, P. M., Bentley, D. R. and Giannelli, F. (1993) Determination of the organisation of coding sequences within the iduronate sulphate sulphatase (IDS) gene. Hum Mol Genet 2(1):5-10.

Gliemann, J. (1998) Receptors of the low density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands. Biol Chem 379(8-9):951-64.

Gort, L., Chabas, A. and Coll, M. J. (1998) Hunter disease in the Spanish population: molecular analysis in 31 families. J Inherit Metab Dis 21(6):655-61.

Harmatz, P., Kramer, W. G., Hopwood, J. J., Simon, J., Butensky, E. and Swiedler, S. J. (2005) Pharmacokinetic profile of recombinant human N-acetylgalactosamine 4-sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): a phase I/II study. Acta Paediatr Suppl 94(447):61-8; discussion 57.

Herz, J., Kowal, R. C., Goldstein, J. L. and Brown, M. S. (1990) Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compartment. Embo J 9(6):1769-76.

Hille-Rehfeld, A. (1995) Mannose 6-phosphate receptors in sorting and transport of lysosomal enzymes. Biochim Biophys Acta 1241(2):177-94.

Hwang, J., Fitzgerald, D. J., Adhya, S. and Pastan, I. (1987) Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli. Cell 48(1):129-36.

Iglewski, B.H., Liu, P.V., Kabat, D. (1977) Mechanism of action of Pseudomonas aeruginosa exotoxin A: adenosine diphosphate-ribosylation of mammalian elongation factor 2 in vitro and in vivo. Infection and Immunity 15:138-144.


Isogai, K., Sukegawa, K., Tomatsu, S., Fukao, T., Song, X. Q., Yamada, Y., Fukuda, S., Orii, T. and Kondo, N. (1998) Mutation analysis in the iduronate-2-sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease). J Inherit Metab Dis 21(1):60-70.

Jiang, K., Watson D.J., and Wolfe, J.H. (2005) A genetic fusion construct between the tetanus toxin C fragment and the lysosomal acid hydrolase b-glucuronidase expresses a bifunctional protein with enhanced secretion and neuronal uptake. J Neurochem 93:1334-1344.

Kakkis, E. D., Muenzer, J., Tiller, G. E., Waber, L., Belmont, J., Passage, M., Izykowski, B., Phillips, J., Doroshow, R., Walot, I., Hoft, R. and Neufeld, E. F. (2001) Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 344(3):182-8.

Kaplan, A., Achord, D. T. and Sly, W. S. (1977) Phosphohexosyl components of a lysosomal enzyme are recognized by pinocytosis receptors on human fibroblasts. Proc Natl Acad Sci USA 74(5):2026-30.

Karsten, S., Voskoboeva, E., Tishkanina, S., Pettersson, U., Krasnopolskaja, X. and Bondeson, M. L. (1998) Mutational spectrum of the iduronate-2-sulfatase (IDS) gene in 36 unrelated Russian MPS II patients. Hum Genet 103(6):732-5.

Kornfeld, S. (1986) Trafficking of the lysosomal enzyme in normal and disease states. J Clin Invest 77(1):1-6.

Kornfeld, S. (1990) Lysosomal enzyme targeting. Biochem Soc Trans 18(3):367-74.

Kornfeld, S. (1992) Structure and function of the mannose 6-phosphate/insulinlike growth factor II receptors. Annu Rev Biochem 61:307-30.

Kounnas, M. Z., Morris, R. E., Thompson, M. R., FitzGerald, D. J., Strickland, D. K. and Saelinger, C. B. (1992) The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem 267(18):12420-3.

Lee-Chen, G. J., Lin, S. P., Lin, S. Z., Chuang, C.K., Hsiao, K. T., Huang, C. F. and Lien, W. C. (2002) Identification and characterization of mutations underlying Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB). J Med Genet 39:E3.

Li, P., Thompson, J. N., Hug, G., Huffman, P. and Chuck, G. (1996) Biochemical and molecular analysis in a patient with the severe form of Hunter syndrome after bone marrow transplantation. Am J Med Genet 64(4):531-5.

Li, P., Bellows, A. and Thompson, J. N. (1999) Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome). J Med Genet 36(1):21-7.

Lin, S. P., Chuang, C. K., Tsai, P. J., Chang, J. G. and Wraith, J. E. (2000) Molecular basis of mucopolysaccharidosis type II in Taiwan Chinese. Euro J Hum Genet Poster A: P-183.

Li, Y., Wood, N., Donnelly, P. and Yellowlees, D. (1998) Cell density and oestrogen both stimulate alpha 2-macroglobulin receptor expression in breast cancer cell T-47D. Anticancer Res 18(2A):1197-202.

Lin, X. (2004) Functions of heparan sulfate proteoglycans in cell signaling during development. Development 131(24):6009-21.

Lissens, W., Zenati, A. and Liebaers, I. (1984) Polyclonal antibodies against iduronate 2-sulphate sulphatase from human urine. Biochim Biophys Acta 801(3):365-71.

Lissens, W., Seneca, S. and Liebaers, I. (1997) Molecular analysis in 23 Hunter disease families. J Inher Metab Dis 20(3):453-6.

Liu, P.V. (1966) The roles of various fractions of Pseudomonas aeruginosa in its pathogenesis. III. Identity of the lethal toxins produced in vitro and in vivo. J Infect Dis 116:481-489.

Malmgren, H., Carlberg, B. M., Pettersson, U. and Bondeson, M. L. (1995) Identification of an alternative transcript from the human iduronate-2-sulfatase (IDS) gene. Genomics 29(1):291-3.

Malmstrom, A., Roden, L., Feingold, D. S., Jacobsson, I., Backstrom, G. and Lindahl, U. (1980) Biosynthesis of heparin. Partial purification of the uronosyl C-5 epimerase. J Biol Chem 255(9):3878-83.

McKinnis, E. J., Sulzbacher, S., Rutledge, J. C., Sanders, J. and Scott, C. R. (1996) Bone marrow transplantation in Hunter syndrome. J Pediatr 129(1):145-8.

Meikle, P. J., Fietz, M. J. and Hopwood, J. J. (2004) Diagnosis of lysosomal storage disorders: current techniques and future directions. Expert Rev Mol Diagn 4(5):677-91.

Miebach, E. (2005) Enzyme replacement therapy in mucopolysaccharidosis type I. Acta Paediatr Suppl 94(447):58-60; discussion 57.

Millat, G., Froissart, R., Maire, I. and Bozon, D. (1997) Characterization of iduronate sulphatase mutants affecting N-glycosylation sites and the cysteine-84 residue. Biochem J 326:43-7.

Millat, G., Froissart, R., Maire, I. and Bozon, D. (1997) IDS transfer from overexpressing cells to IDS-deficient cells. Exp Cell Res 230(2):362-7.

Millat, G., Froissart, R., Cudry, S., Bonnet, V., Maire, I. and Bozon, D. (1998) COS cell expression studies of P86L, P86R, P480L and P480Q Hunter's disease-causing mutations. Biochim Biophys Acta 1406(2):214-8.

Moestrup, S. K., Gliemann, J. and Pallesen, G. (1992) Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res 269(3):375-82.

Moskowitz, S. M., Tieu, P. T. and Neufeld, E. F. (1993) A deletion/insertion mutation in the IDUA gene in a Libyan Jewish patient with Hurler syndrome (mucopolysaccharidosis IH). Hum Mutat 2(1):71-3.

Muenzer, J., Lamsa, J. C., Garcia, A., Dacosta, J., Garcia, J. and Treco, D. A. (2002) Enzyme replacement therapy in mucopolysaccharidosis type II (Hunter syndrome): a preliminary report. Acta Paediatr Suppl 91(439):98-9.

Mullen, C. A., Thompson, J. N., Richard, L. A. and Chan, K. W. (2000) Unrelated umbilical cord blood transplantation in infancy for mucopolysaccharidosis type IIB (Hunter syndrome) complicated by autoimmune hemolytic anemia. Bone Marrow Transplant 25(10):1093-7.

Munier-Lehmann, H., Mauxion, F. and Hoflack, B. (1996) Function of the two mannose 6-phosphate receptors in lysosomal enzyme transport. Biochem Soc Trans 24(1):133-6.

Neufeld, E. F. (1991) Lysosomal storage diseases. Annu Rev Biochem 60:257-80.

Neufeld, E. F. and Muenzer, J. (1995) The mucopolysaccharidoses. In: Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D. eds. The metabolic basis of inherited diseases. 7th ed. New York: McGraw-Hill, 2465-94.

Nakayama, K. and Wakatsuki, S. (2003) The structure and function of GGAs, the traffic controllers at the TGN sorting crossroads. Cell Struct Funct 28(5):431-42.

Pan, D., Shankar, R., Stroncek, D. F. and Whitley, C. B. (1999) Combined ultrafiltration-transduction in a hollow-fiber bioreactor facilitates retrovirus-mediated gene transfer into peripheral blood lymphocytes from patients with mucopolysaccharidosis type II. Hum Gene Ther 10(17):2799-810.

Paulsson, M. and Heinegard, D. (1984) Noncollagenous cartilage proteins current status of an emerging research field. Coll Relat Res 4(3):219-29.

Peters, C. and Krivit, W. (2000) Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome). Bone Marrow Transplant 25(10):1097-9.

Petruschka, L., Zschiesche, M., Bielicki, J., Seidlitz, G., Machill, G., Hopwood, J. J. and Herrmann, F. H. (1994) Mucopolysaccharidosis type II (Hunter syndrome): characterization of the iduronate-2-sulphatase in MPS II skin fibroblasts. J Inherit Metab Dis 17(1):89-92.

Poorthuis, B. J., Wevers, R. A., Kleijer, W. J., Groener, J. E., de Jong, J. G., van Weely, S., Niezen-Koning, K. E. and van Diggelen, O. P. (1999) The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 105(1-2):151-6.

Rathmann, M., Bunge, S., Steglich, C., Schwinger, E. and Gal, A. (1995) Evidence for an iduronate-sulfatase pseudogene near the functional Hunter syndrome gene in Xq27.3-q28. Hum Genet 95(1):34-8.

Rathmann, M., Bunge, S., Beck, M., Kresse, H., Tylki-Szymanska, A. and Gal, A. (1996) Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene. Am J Hum Genet 59(6):1202-9.

Ricci, V., Filocamo, M., Regis, S., Corsolini, F., Stroppiano, M., Duca, M. D. and Gatti, R. (2003) Expression studies of two novel in CIS-mutations identified in an intermediate case of Hunter syndrome. Am J Med Genet 120(1):84-7.

Sandy, J. D., Brown, H. L. and Lowther, D. A. (1978) Degradation of proteoglycan in articular cartilage. Biochim Biophys Acta 543(4):536-44.

Spiro, R. G. (2004) Role of N-linked polymannose oligosaccharides in targeting glycoproteins for endoplasmic reticulum-associated degradation. Cell Mol Life Sci 61(9):1025-41.

Stenson, P. D., Ball, E. V., Mort, M., Phillips, A. D., Shiel, J. A., Thomas, N. S., Abeysinghe, S., Krawczak, M. and Cooper, D. N. (2003) Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 21(6):577-81.

Strickland, D. K. and Ranganathan, S. (2003) Diverse role of LDL receptor-related protein in the clearance of proteases and in signaling. J Thromb Haemost 1(7):1663-70.

Stroncek, D. F., Hubel, A., Shankar, R. A., Burger, S. R., Pan, D., McCullough, J. and Whitley, C. B. (1999) Retroviral transduction and expansion of peripheral blood lymphocytes for the treatment of mucopolysaccharidosis type II, Hunter's syndrome. Transfusion 39(4):343-50.

Sukegawa, K., Tomatsu, S., Fukao, T., Iwata, H., Song, X. Q., Yamada, Y., Fukuda, S., Isogai, K. and Orii, T. (1995) Mucopolysaccharidosis type II (Hunter disease): identification and characterization of eight point mutations in the iduronate-2-sulfatase gene in Japanese patients. Hum Mutat 6(2):136-43.

Sun H., Yang M., Haskins M. et al. (1999) Retrovirus vector-mediated correction and cross-correction of lysosomal alpha-mannosidase deficiency in human and feline fibroblasts. Hum. Gene Ther. 10, 1311–1319.

Timms, K. M., Lu, F., Shen, Y., Pierson, C. A., Muzny, D. M., Gu, Y., Nelson, D. L. and Gibbs, R. A. (1995) 130 kb of DNA sequence reveals two new genes and a regional duplication distal to the human iduronate-2-sulfate sulfatase locus. Genome Res 5(1):71-8.

Tong, P. Y. and Kornfeld, S. (1989) Ligand interactions of the cation-dependent mannose 6-phosphate receptor. Comparison with the cation-independent mannose 6-phosphate receptor. J Biol Chem 264(14):7970-5.

Truppe, W. and Kresse, H. (1978) Uptake of proteoglycans and sulfated glycosaminoglycans by cultured skin fibroblasts. Eur J Biochem 85(2):351-6.

Vafiadaki, E., Cooper, A., Heptinstall, L. E., Hatton, C. E., Thornley, M. and Wraith, J. E. (1998) Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease). Arch Dis Child 79(3):237-41.

Vellodi, A., Young, E., Cooper, A., Lidchi, V., Winchester, B. and Wraith, J. E. (1999) Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis 22(5):638-48.

Villani, G. R., Daniele, A., Balzano, N. and Di Natale, P. (2000) Expression of five iduronate-2-sulfatase site-directed mutations. Biochim Biophys Acta 1501(2-3):71-80.

Voznyi, Y. V., Keulemans, J. L. and van Diggelen, O. P. (2001) A fluorimetric enzyme assay for the diagnosis of MPS II (Hunter disease). J Inherit Metab Dis 24(6):675-80.

Walkley, S. U. (1998) Cellular pathology of lysosomal storage disorders. Brain Pathol 8(1):175-93.

Wasteson, A. and Neufeld, E. F. (1982) Iduronate sulfatase from human plasma. Methods Enzymol 83:573-8.

Weaver, A. M., McCabe, M., Kim, I., Allietta, M. M. and Gonias, S. L. (1996) Epidermal growth factor and platelet-derived growth factor-BB induce a stable increase in the activity of low density lipoprotein receptor-related protein in vascular smooth muscle cells by altering receptor distribution and recycling. J Biol Chem 271(40):24894-900.

Whitley, C. B., McIvor, R. S., Aronovich, E. L., Berry, S. A., Blazar, B. R., Burger, S. R., Kersey, J. H., King, R. A., Faras, A. J., Latchaw, R. E., McCullough, J., Pan, D., Ramsay, N. K. and Stroncek, D. F. (1996) Retroviral-mediated transfer of the iduronate-2-sulfatase gene into lymphocytes for treatment of mild Hunter syndrome (mucopolysaccharidosis type II). Hum Gene Ther 7(4):537-49.

Wilkie, A. O., Amberger, J. S. and McKusick, V. A. (1994) A gene map of congenital malformations. J Med Genet 31(7):507-17.

Willnow, T. E. and Herz, J. (1994) Genetic deficiency in low density lipoprotein receptor-related protein confers cellular resistance to Pseudomonas exotoxin A. Evidence that this protein is required for uptake and degradation of multiple ligands. J Cell Sci 107:719-26.

Wilson, P. J., Meaney, C. A., Hopwood, J. J. and Morris, C. P. (1993) Sequence of the human iduronate 2-sulfatase (IDS) gene. Genomics 17(3):773-5.

Wilson, P. J., Morris, C. P., Anson, D. S., Occhiodoro, T., Bielicki, J., Clements, P. R. and Hopwood, J. J. (1990) Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. Proc Natl Acad Sci USA 87(21):8531-5.

References

Brown, M. S. and Goldstein, J. L. (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232(4746):34-47.

Cai, H. J., Fan, L. M., Huang, M. G., Chen, X. Y., Liu, G. Q. and Chen, Q. (1985) Homozygous familial hypercholesterolemic patients in China. Atherosclerosis 57(2-3):303-12.

Castelli, W. P., Doyle, J. T., Gordon, T., Hames, C. G., Hjortland, M. C., Hulley, S. B., Kagan, A. and Zukel, W. J. (1977) HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation 55(5):767-72.

Champe, P.C., and Harvey, R.A. (1994) Cholesterol and steroid metabolism. In Lippincott’s illustrated reviews: biochemistry. 2nd ed. Edited by P.C. Champe and R.A. Harvey. J.B. Lippincott Company, Philadelphia, Pa. pp. 205–228.

Chen, W. J., Goldstein, J. L. and Brown, M. S. (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 265(6):3116-23.

Cotran, R.S., Kumar, V., and Robbins. S.L. (1994) In Robbins pathologic basis of disease. 5th ed. Edited by R.S. Cotran, V. Kumar, and S.L. Robbins. W.B. Saunders, Philadephia, Pa. pp. 480-2.

Cummings, R. D., Kornfeld, S., Schneider, W. J., Hobgood, K. K., Tolleshaug, H., Brown, M. S. and Goldstein, J. L. (1983) Biosynthesis of N- and O-linked oligosaccharides of the low density lipoprotein receptor. J Biol Chem 258(24):15261-73.

Day, I. N., Whittall, R. A., O'Dell, S. D., Haddad, L., Bolla, M. K., Gudnason, V. and Humphries, S. E. (1997) Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. Hum Mutat 10(2):116-27.

Ekstrom, U., Abrahamson, M., Sveger, T., Lombardi, P. and Nilsson-Ehle, P. (1995) An efficient screening procedure detecting six novel mutations in the LDL receptor gene in Swedish children with hypercholesterolemia. Hum Genet 96(2):147-50.

Ekstrom, U., Abrahamson, M., Sveger, T., Sun, X. M., Soutar, A. K. and Nilsson-Ehle, P. (2000) Expression of an LDL receptor allele with two different mutations (E256K and I402T). Mol Pathol 53(1):31-6.

Elovson, J., Chatterton, J. E., Bell, G. T., Schumaker, V. N., Reuben, M. A., Puppione, D. L., Reeve, J. R., Jr. and Young, N. L. (1988) Plasma very low density lipoproteins contain a single molecule of apolipoprotein B. J Lipid Res 29(11):1461-73.

Fass, D., Blacklow, S., Kim, P. S. and Berger, J. M. (1997) Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module. Nature 388(6643):691-3.

Gaffney, D., Reid, J. M., Cameron, I. M., Vass, K., Caslake, M. J., Shepherd, J. and Packard, C. J. (1995) Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler Thromb Vasc Biol 15(8):1025-9.

Genest, J. Jr. (2002) Genetics and prevention: a new look at high-density lipoprotein cholesterol. Cardiol Rev 10(1):61-71.

Goldstein, J., Hobbs, H. and Brown, M. (1995) Familial hypercholesterolemia. In The Metabolic Basis of Inherited Diseases. 6th edition. Scriver, E. R., Beaudet, A. L., Sly, W. S. and Valle, D. editors. McGraw-Hill Book Co., New York. 1981–2030.

Goldstein, J., Hobbs, H. and Brown, M. (2001) Familial hypercholesterolemia. In The Metabolic and Molecular Bases of Inherited Disease. Valle, D. ed. Vol 2. 8th ed. New York, NY:McGraw-Hill. 2863–913.

Goldstein, J. L. and Brown, M. S. (2001) Molecular medicine. The cholesterol quartet. Science 292(5520):1310-2.

Huang, Ai-Chun. (2001) Molecular studies of Familial Hypercholesterolemia. National Taiwan Normal University Master thesis.

Hobbs, H. H., Russell, D. W., Brown, M. S. and Goldstein, J. L. (1990) The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24:133-70.

Hobbs, H. H., Brown, M. S. and Goldstein, J. L. (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1(6):445-66.

Howell, B. W., Lanier, L. M., Frank, R., Gertler, F. B. and Cooper, J. A. (1999) The disabled 1 phosphotyrosine-binding domain binds to the internalization signals of transmembrane glycoproteins and to phospholipids. Mol Cell Biol 19(7):5179-88.

Innerarity, T. L., Weisgraber, K. H., Arnold, K. S., Mahley, R. W., Krauss, R. M., Vega, G. L. and Grundy, S. M. (1987) Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 84(19):6919-23.

Khoo, K. L., van Acker, P., Defesche, J. C., Tan, H., van de Kerkhof, L., Heijnen-van Eijk, S. J., Kastelein, J. J. and Deslypere, J. P. (2000) Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia. Clin Genet 58(2):98-105.

Kotze, M. J., Loubser, O., Thiart, R., de Villiers, J. N., Langenhoven, E., Theart, L., Steyn, K., Marais, A. D. and Raal, F. J. (1997) CpG hotspot mutations at the LDL receptor locus are a frequent cause of familial hypercholesterolaemia among South African Indians. Clin Genet 51(6):394-8.

Lee, L. Y., Mohler, W. A., Schafer, B. L., Freudenberger, J. S., Byrne-Connolly, N., Eager, K. B., Mosley, S. T., Leighton, J. K., Thrift, R. N., Davis, R. A. and et al. (1989) Nucleotide sequence of the rat low density lipoprotein receptor cDNA. Nucleic Acids Res 17(3):1259-60.

Lehrman, M. A., Schneider, W. J., Sudhof, T. C., Brown, M. S., Goldstein, J. L. and Russell, D. W. (1985) Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227(4683):140-6.

Lehrman, M. A., Goldstein, J. L., Russell, D. W. and Brown, M. S. (1987) Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. Cell 48(5):827-35.

Leitersdorf, E., Tobin, E. J., Davignon, J. and Hobbs, H. H. (1990) Common low-density lipoprotein receptor mutations in the French Canadian population. J Clin Invest 85(4):1014-23.

Levy, R. I. (1981) Declining mortality in coronary heart disease. Arteriosclerosis 1(5):312-25.

Lin, W. L., Tai, D. Y., Lo, E., Lee-Chen, G. J. (2002) The mutation underlying familial hypercholesterolemia in a Taiwanese family. BioFormosa 37(1):1-6.

Lougheed, M. and Steinbrecher, U. P. (1996) Mechanism of uptake of copper-oxidized low density lipoprotein in macrophages is dependent on its extent of oxidation. J Biol Chem 271(20):11798-805.

Lund, H., Takahashi, K., Hamilton, R. L. and Havel, R. J. (1989) Lipoprotein binding and endosomal itinerary of the low density lipoprotein receptor-related protein in rat liver. Proc Natl Acad Sci U S A 86(23):9318-22.

Mak, Y. T., Pang, C. P., Tomlinson, B., Zhang, J., Chan, Y. S., Mak, T. W. and Masarei, J. R. (1998) Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients. Arterioscler Thromb Vasc Biol 18(10):1600-5.

Manninen, V., Tenkanen, L., Koskinen, P., Huttunen, J. K., Manttari, M., Heinonen, O. P. and Frick, M. H. (1992) Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation 85(1):37-45.

Maruyama, T., Miyake, Y., Tajima, S., Harada-Shiba, M., Yamamura, T., Tsushima, M., Kishino, B., Horiguchi, Y., Funahashi, T., Matsuzawa, Y. and et al. (1995) Common mutations in the low-density-lipoprotein-receptor gene causing familial hypercholesterolemia in the Japanese population. Arterioscler Thromb Vasc Biol 15(10):1713-8.

Mayes, P.A. (1998) Cholesterol synthesis, transport, and excretion. In Harper’s biochemistry. 23rd ed. Edited by R.K. Murray, D.K. Granner, P.A. Mayes, and V.W. Rodwell. Appleton & Lange, Norwalk, Conn. pp. 266-78.

Pimstone, S. N., Sun, X. M., du Souich, C., Frohlich, J. J., Hayden, M. R. and Soutar, A. K. (1998) Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol 18(2):309-15.

Pittman, R. C., Carew, T. E., Attie, A. D., Witztum, J. L., Watanabe, Y. and Steinberg, D. (1982) Receptor-dependent and receptor-independent degradation of low density lipoprotein in normal rabbits and in receptor-deficient mutant rabbits. J Biol Chem 257(14):7994-8000.

Pullinger, C. R., Hennessy, L. K., Chatterton, J. E., Liu, W., Love, J. A., Mendel, C. M., Frost, P. H., Malloy, M. J., Schumaker, V. N. and Kane, J. P. (1995) Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest 95(3):1225-34.

Rubinsztein, D. C., Jialal, I., Leitersdorf, E., Coetzee, G. A. and van der Westhuyzen, D. R. (1993) Identification of two new LDL-receptor mutations causing homozygous familial hypercholesterolemia in a South African of Indian origin. Biochim Biophys Acta 1182(1):75-82.

Russell, D. W., Schneider, W. J., Yamamoto, T., Luskey, K. L., Brown, M. S. and Goldstein, J. L. (1984) Domain map of the LDL receptor: sequence homology with the epidermal growth factor precursor. Cell 37(2):577-85.

Russell, D. W., Lehrman, M. A., Sudhof, T. C., Yamamoto, T., Davis, C. G., Hobbs, H. H., Brown, M. S. and Goldstein, J. L. (1986) The LDL receptor in familial hypercholesterolemia: use of human mutations to dissect a membrane protein. Cold Spring Harb Symp Quant Biol 51 Pt 2(811-9.

Soutar, A. K. (1998) Update on low density lipoprotein receptor mutations. Curr Opin Lipidol 9(2):141-7.

Soutar, A. K., Naoumova, R. P. and Traub, L. M. (2003) Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol 23(11):1963-70.

Spady, D. K. and Dietschy, J. M. (1983) Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res 24(3):303-15.

Suckling, K. E. and Stange, E. F. (1985) Role of acyl-CoA: cholesterol acyltransferase in cellular cholesterol metabolism. J Lipid Res 26(6):647-71.

Sudhof, T. C., Goldstein, J. L., Brown, M. S. and Russell, D. W. (1985) The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228(4701):815-22.

Sun, X. M., Patel, D. D., Webb, J. C., Knight, B. L., Fan, L. M., Cai, H. J. and Soutar, A. K. (1994) Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype. Arterioscler Thromb 14(1):85-94.

Toshima, S., Hasegawa, A., Kurabayashi, M., Itabe, H., Takano, T., Sugano, J., Shimamura, K., Kimura, J., Michishita, I., Suzuki, T. and Nagai, R. (2000) Circulating oxidized low density lipoprotein levels. A biochemical risk marker for coronary heart disease. Arterioscler Thromb Vasc Biol 20(10):2243-7.

Varret, M., Rabes, J. P., Thiart, R., Kotze, M. J., Baron, H., Cenarro, A., Descamps, O., Ebhardt, M., Hondelijn, J. C., Kostner, G. M., Miyake, Y., Pocovi, M., Schmidt, H., Schuster, H., Stuhrmann, M., Yamamura, T., Junien, C., Beroud, C. and Boileau, C. (1998) LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis. Nucl Acid Res 26(1):248-252.

Villeger, L., Abifadel, M., Allard, D., Rabes, J. P., Thiart, R., Kotze, M. J., Beroud, C., Junien, C., Boileau, C. and Varret, M. (2002) The UMD-LDLR database: additions to the software and 490 new entries to the database. Hum Mutat 20(2):81-7.

Yamamoto, T., Davis, C. G., Brown, M. S., Schneider, W. J., Casey, M. L., Goldstein, J. L. and Russell, D. W. (1984) The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 39(1):27-38.

Yamamoto, T., Bishop, R. W., Brown, M. S., Goldstein, J. L. and Russell, D. W. (1986) Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit. Science 232(4755):1230-7.

Yeagle, P. L. (1988) Cholesterol and the cell membrane. In Biology of Cholesterol (Yeagle, P., ed) pp. 121-146, CRC Press, Boca Raton, Florida 3. Fielding, C. J.
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