施奈德结晶状角膜营养不良致病基因功能的研究进展

doi:10.3877/cma.j.issn.2095-2007.2021.05.008

施奈德结晶状角膜营养不良(SCCD)是一种罕见的常染色体显性遗传病，临床症状为角膜中脂质异常积累。有研究结果表明，SCCD由UbiA异戊烯基转移酶结构域包含蛋白1(UBIAD1)基因突变引起。UBIAD1突变后分子构型改变，不能与3-羟基-3-甲基戊二酸单酰辅酶A还原酶受体(HMGCR)解离，HMGCR不能通过泛素化途径降解，导致HMGCR在内质网膜聚集，胆固醇合成增多，诱发SCCD疾病。本文中笔者就UBIAD1的功能和SCCD致病的分子机制进行重点综述，旨在为SCCD的诊断与治疗提供参考。

关键词: 施奈德结晶状角膜营养不良, UbiA异戊烯基转移酶结构域包含蛋白1, 胆固醇生物合成, 脂质代谢

Schneider′s crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by abnormal accumulation of lipids in the cornea. SCCD is caused by mutations in the UbiA isopentenyl transferase domain containing protein 1 (UBIAD1) gene. After UBIAD1 mutation, the molecular configuration changed, and then could not dissociate from 3-hydroxy-3-methylglutarate monoacyl-CoA reductase receptor (HMGCR). HMGCR could not be degraded through ubiquitin pathway, resulting in HMGCR aggregation in the endoplasmic reticulum, which increased cholesterol synthesis and caused SCCD. In this paper, the function of UBIAD1 and the molecular mechanism of SCCD pathogenesis were reviewed, which could provide the reference for the diagnosis and treatment of SCCD.

Key words: Schnyder′s crystalline corneal dystrophy, UbiA prenyltransferase domain contain-ing 1, Cholesterol biosynthesis, Lipid metabolism

表1 导致SCCD疾病的UBIAD1基因突变位点

序号	突变位点	突变类型	参考文献
1	75	Ser-Phe	[23]
2	97	Ala-Thr	[29]
3	98^#	Gly-Ser	[38]
4	102^*#	Asn-Ser	[17，20，23，25，29，32]
5	103	Thr-Ile	[32]
6	112	Asp-Gly	[23]
7	112	Asp-Asn	[29，33，40]
8	118	Asp-Gly	[20]
9	119	Arg-Gly	[23，25]
10	120	Thr-Arg	[40]
11	121	Leu-Phe	[20，25，40]
12	121	Leu-Val	[29]
13	122	Val-Glu	[29]
14	122	Val-Gly	[29]
15	171^#	Ser-Pro	[20，29，33]
16	174	Tyr-Cys	[20，29]
17	175	Thr-Ile	[20，23，24，29]
18	176	Gly-Glu	[40]
19	177	Gly-Arg	[17，29]
20	177	Gly-Glu	[33，40]
21	181	Lys-Arg	[20]
22	186	Gly-Arg	[20]
23	188	Leu-His	[29]
24	190	Ile-Thr	[33]
25	232	Asn-ser	[23，29]
26	233	Asn-His	[20，29]
27	236	Asp-Glu	[20，24，29]
28	240	Asp-Asn	[33]

表1 导致SCCD疾病的UBIAD1基因突变位点

序号	突变位点	突变类型	参考文献
1	75	Ser-Phe	[23]
2	97	Ala-Thr	[29]
3	98^#	Gly-Ser	[38]
4	102^*#	Asn-Ser	[17，20，23，25，29，32]
5	103	Thr-Ile	[32]
6	112	Asp-Gly	[23]
7	112	Asp-Asn	[29，33，40]
8	118	Asp-Gly	[20]
9	119	Arg-Gly	[23，25]
10	120	Thr-Arg	[40]
11	121	Leu-Phe	[20，25，40]
12	121	Leu-Val	[29]
13	122	Val-Glu	[29]
14	122	Val-Gly	[29]
15	171^#	Ser-Pro	[20，29，33]
16	174	Tyr-Cys	[20，29]
17	175	Thr-Ile	[20，23，24，29]
18	176	Gly-Glu	[40]
19	177	Gly-Arg	[17，29]
20	177	Gly-Glu	[33，40]
21	181	Lys-Arg	[20]
22	186	Gly-Arg	[20]
23	188	Leu-His	[29]
24	190	Ile-Thr	[33]
25	232	Asn-ser	[23，29]
26	233	Asn-His	[20，29]
27	236	Asp-Glu	[20，24，29]
28	240	Asp-Asn	[33]

图1 UbiA异戊烯基转移酶结构域包含蛋白1在维生素K2生物合成中作用的示意图

图3 胆固醇和甲基萘醌-4生物合成途径的示意图

[1]	Weiss JS. Schnyder corneal dystrophy[J]. Curr Opin Ophthalmol, 2009, 20(4): 292-298.
[2]	Weiss JS. More on Schnyder corneal dystrophy[J]. Ophthalmology, 2009, 116(11): 2260.
[3]	Wibaut F, Van Went JM. A strange inherited corneal alteration[J]. Ned Tijdschr Geneeskd, 1924, 68: 2996-2997.
[4]	Schnyder WF. Report about a new type of familial corneal disorder[J]. Schweiz Med Wschr, 1929, 10: 559-571.
[5]	Schnyder WF. Disk-like inherited crytstalline inclusions in the corneal center[J]. KIin Monatsbl Augenheilkd, 1939, 103: 494-502.
[6]	Glees M. Corneal crystalline dystrophy[J]. Klin Monbl Augenheilkd Augenarztl Fortbild, 1957, 131(6): 721-724.
[7]	Bron AJ, Williams HP, Carruthers ME. Hereditary crystalline stromal dystrophy of Schnyder. Ⅰ. Clinical features of a family with hyperlipoproteinaemia[J]. Br J Ophthalmol, 1972, 56(5): 383-399.
[8]	Garner A, Tripathi RC. Hereditary crystalline stromal dystrophy of Schnyder Ⅱ. Histopathology and ultrastructure[J]. Br J Ophthalmol, 1972, 56(5): 400-408.
[9]	Thiel HJ, Voigt GJ, Parwaresch MR. Crystalline corneal dystrophy (Schnyder) in the presence of familial type Ⅱa hyperlipoproteinaemia[J]. Klin Monbl Augenheilkd, 1977, 171(5): 678-684.
[10]	Burns RP, Connor W, Gipson I. Cholesterol turnover in hereditary crystalline corneal dystrophy of Schnyder[J]. Trans Am Ophthalmol Soc, 1978, 76: 184-196.
[11]	Roth AM, Ekins MB, Waring GO, et al. Oval corneal opacities in beagles. III. Histochemical demonstration of stromal lipids without hyperlipidemia[J]. Invest Ophthalmol Vis Sci, 1981, 21(1): 95-106.
[12]	Lisch W, Weidle EG, Lisch C, et al. Schnyder′s dystrophy: Progression and metabolism[J]. Ophthalmic Paediatr Genet, 1986, 7(1): 45-56.
[13]	Rodrigues MM, Kruth HS, Krachmer JH, et al. Unesterified cholesterol in Schnyder′s corneal crystalline dystrophy[J]. Am J Ophthalmol, 1987, 104(2): 157-163.
[14]	Rodrigues MM, Kruth HS, Krachmer JH, et al. Cholesterol localization in ultrathin frozen sections in Schnyder′s corneal crystalline dystrophy[J]. Am J Ophthalmol, 1990, 110(5): 513-517.
[15]	Brownstein S, Jackson WB, Onerheim RM. Schnyder′s crystalline corneal dystrophy in association with hyperlipoproteinemia: histopathological and ultrastructural findings[J]. Can J Ophthalmol, 1991, 26(5): 273-279.
[16]	McCarthy M, Innis S, Dubord P, et al. Panstromal Schnyder corneal dystrophy. A clinical pathologic report with quantitative analysis of corneal lipid composition[J]. Ophthalmology, 1994, 101(5): 895-901.
[17]	Weiss JS. Visual morbidity in thirty-four families with Schnyder crystalline corneal dystrophy (an American Ophthalmological Society thesis)[J]. Trans Am Ophthalmol Soc, 2007, 105: 616-648.
[18]	Takeuchi T, Furihata M, Heng HH, et al. Chromosomal mapping and expression of the human B120 gene[J]. Gene, 1998, 213(1-2): 189-193.
[19]	Auw-Hadrich C, Witschel H. Corneal dystrophies in the light of modern molecular genetic research[J]. Ophthalmologe, 2002, 99(6): 418-426.
[20]	Riebeling P, Polz S, Tost F, et al. Schnyder′s crystalline corneal dystrophy: Further narrowing of the linkage interval at chromosome 1p34.1—p36[J]. Ophthalmologe, 2003, 100(11): 979-983.
[21]	Shearman AM, Hudson TJ, Andresen JM, et al. The gene for Schnyder′s crystalline corneal dystrophy maps to human chromosome 1p34.1—p36[J]. Hum Mol Genet, 1996, 5(10): 1667-1672.
[22]	Theendakara V, Tromp G, Kuivaniemi H, et al. Fine mapping of the Schnyder′s crystalline corneal dystrophy locus[J]. Hum Genet, 2004, 114(6): 594-600.
[23]	Orr A, Dube MP, Marcadier J, et al. Mutations in the UBIAD1 gene, encoding a potential prenyltransferase, are causal for Schnyder crystalline corneal dystrophy[J]. PLoS One, 2007, 2(8): e685.
[24]	Weiss JS, Kruth HS, Kuivaniemi H, et al. Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause Schnyder crystalline corneal dystrophy[J]. Invest Ophthalmol Vis Sci, 2007, 48(11): 5007-5012.
[25]	Yellore VS, Khan MA, Bourla N, et al. Identification of mutations in UBIAD1 following exclusion of coding mutations in the chromosome 1p36 locus for Schnyder crystalline corneal dystrophy[J]. Mol Vis, 2007, 13: 1777-1782.
[26]	McGarvey TW, Nguyen T, Tomaszewski JE, et al. Isolation and characterization of the TERE1 gene, a gene down-regulated in transitional cell carcinoma of the bladder[J]. Oncogene, 2001, 20(9): 1042-1051.
[27]	McGarvey TW, Nguyen T, Puthiyaveettil R, et al. TERE1, a novel gene affecting growth regulation in prostate carcinoma[J]. Prostate, 2003, 54(2): 144-155.
[28]	McGarvey TW, Nguyen TB, Malkowicz SB. An interaction between apolipoprotein E and TERE1 with a possible association with bladder tumor formation[J]. J Cell Biochem, 2005, 95(2): 419-428.
[29]	Nickerson ML, Kostiha BN, Brandt W, et al. UBIAD1 mutation alters a mitochondrial prenyltransferase to cause Schnyder corneal dystrophy[J]. PLoS One, 2010, 5(5): e10760.
[30]	Weiss JS. Schnyder′s dystrophy of the cornea[J]. A Swede-Finn connection. Cornea, 1992, 11(2): 93-101.
[31]	Weiss JS, Khemichian AJ. Differential diagnosis of Schnyder corneal dystrophy[J]. Dev Ophthalmol, 2011, 48: 67-96.
[32]	Weiss JS, Kruth HS, Kuivaniemi H, et al. Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function[J]. Am J Med Genet A, 2008, 146A(3): 271-283.
[33]	Weiss JS, Wiaux C, Yellore V, et al. Newly reported p. Asp240Asn mutation in UBIAD1 suggests central discoid corneal dystrophy is a variant of Schnyder corneal dystrophy[J]. Cornea, 2010, 29(7): 777-780.
[34]	Weiss JS. Schnyder crystalline dystrophy sine crystals. Recommendation for a revision of nomenclature[J]. Ophthalmology, 1996, 103(3): 465-473.
[35]	Weiss JS. Corneal dystrophy classification[J]. Ophthalmology, 2009, 116(5): 1013-1014.
[36]	Weiss JS, Moller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies[J]. Cornea, 2008, 27(S2): S1-83.
[37]	Weiss JS, Moller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies[J]. Cornea, 2015, 34(2): 117-159.
[38]	Jing Y, Liu C, Xu J, et al. A novel UBIAD1 mutation identified in a Chinese family with Schnyder crystalline corneal dystrophy[J]. Mol Vis, 2009, 15: 1463-1469.
[39]	Jing Y, Wang L. Morphological evaluation of Schnyder′s crystalline corneal dystrophy by laser scanning confocal microscopy and Fourier-domain optical coherence tomography[J]. Clin Exp Ophthalmol, 2009, 37(3): 308-312.
[40]	Kitazawa K, Wakimasu K, Kayukawa K, et al. Long-term outcome after penetrating keratoplasty in a pedigree with the G177E mutation in the UBIAD1 gene for Schnyder corneal dystrophy[J]. Cornea, 2018, 37(5): 554-559.
[41]	Nakagawa K, Hirota Y, Sawada N, et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme[J]. Nature, 2010, 468(7320): 117-121.
[42]	Xia Y, Midoun SZ, Xu Z, et al. Heixuedian (heix), a potential melanotic tumor suppressor gene, exhibits specific spatial and temporal expression pattern during Drosophila hematopoiesis[J]. Dev Biol, 2015, 398(2): 218-230.
[43]	Dragh MA, Xu Z, Al-Allak ZS, et al. Vitamin K2 prevents lymphoma in Drosophila[J]. Sci Rep, 2017, 7(1): 17047.
[44]	Vos M, Esposito G, Edirisinghe JN, et al. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency[J]. Science, 2012, 336(6086): 1306-1310.
[45]	Mugoni V, Postel R, Catanzaro V, et al. Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis[J]. Cell, 2013, 152(3): 504-518.
[46]	Wang X, Wang D, Jing P, et al. A novel Golgi retention signal RPWS for tumor suppressor UBIAD1[J]. PLoS One, 2013, 8(8): e72015.
[47]	Huang Y, Hu Z. UBIAD1 protects against oxygen-glucose deprivation/reperfusion-induced multiple subcellular organelles injury through PI3K/AKT pathway in N2A cells[J]. J Cell Physiol, 2018, 233(9): 7480-7496.
[48]	Fredericks WJ, Yin H, Lal P, et al. Ectopic expression of the TERE1 (UBIAD1) protein inhibits growth of renal clear cell carcinoma cells: altered metabolic phenotype associated with reactive oxygen species, nitric oxide and SXR target genes involved in cholesterol and lipid metabolism[J]. Int J Oncol, 2013, 43(2): 638-652.
[49]	Fredericks WJ, McGarvey T, Wang H, et al. The bladder tumor suppressor protein TERE1 (UBIAD1) modulates cell cholesterol: implications for tumor progression[J]. DNA Cell Biol, 2011, 30(11): 851-864.
[50]	Fredericks WJ, Sepulveda J, Lai P, et al. The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes[J]. Oncotarget, 2013, 4(7): 1075-1092.
[51]	Morales CR, Grigoryeva LS, Pan X, et al. Mitochondrial damage and cholesterol storage in human hepatocellular carcinoma cells with silencing of UBIAD1 gene expression[J]. Mol Genet Metab Rep, 2014, 1: 407-411.
[52]	Hirota Y, Nakagawa K, Sawada N, et al. Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1[J]. PLoS One, 2015, 10(4): e0125737.
[53]	Schumacher MM, Elsabrouty R, Seemann J, et al. The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase[J]. eLife, 2015, 4: e05560.
[54]	Johnson BM, DeBose-Boyd RA. Underlying mechanisms for sterol-induced ubiquitination and ER-associated degradation of HMG CoA reductase[J]. Semin Cell Dev Biol, 2018, 81: 121-128.
[55]	Jiang SY, Tang JJ, Xiao X, et al. Schnyder corneal dystrophy-associated UBIAD1 mutations cause corneal cholesterol accumulation by stabilizing HMG-CoA reductase[J]. PLoS Genet, 2019, 15(7): e1008289.
[56]	Jo Y, Hamilton JS, Hwang S, et al. Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice[J]. eLife, 2019, 8: e44396.
[57]	Jun DJ, Schumacher MM, Hwang S, et al. Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation[J]. J Lipid Res, 2020, 61(5): 746-757.
[58]	Li W. Bringing bioactive compounds into membranes: The UbiA superfamily of intramembrane aromatic prenyltransferases[J]. Trends Biochem Sci, 2016, 41(4): 356-370.

[1]	郎琼, 刘长云, 陈雪, 李梅, 丁文玲, 吴春友. 瘦素抵抗与载脂蛋白E基因多态性对儿童血脂的影响[J]. 中华妇幼临床医学杂志(电子版), 2011, 07(01): 9-12.
[2]	童焕军, 汤朝晖, 全志伟. 肝内胆管癌异常脂质代谢研究进展[J]. 中华肝脏外科手术学电子杂志, 2020, 09(06): 501-506.
[3]	邹创欢, 金法, 龙定超. 闭合性颅脑损伤患者脑脊液氧化脂质代谢物的特征及临床意义[J]. 中华脑科疾病与康复杂志(电子版), 2019, 09(04): 201-204.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

Functional research progress of Schneider′s crystalline corneal dystrophy pathogenic gene

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

Functional research progress of Schneider′s crystalline corneal dystrophy pathogenic gene