摘要
进行性对称性红斑角化症的临床表型分析及突变筛查
红斑角化症是一组以广泛分布的红斑(固定或移动)为特征，伴随掌跖角化等表现的疾病，主要有两种临床亚型：可变性红斑角化症(EKV)和进行性对称性红斑角化症(PSEK)，二者均为具有不完全外显率和差异表达的常染色体显性遗传性皮肤病，但其分子发病机制目前仍不清楚。目前仅Ishida-Yamamoto等对PSEK等进行了系列研究，但其研究结果受到了其他学者的怀疑；国内尚无关于PSEK的临床表型及分子遗传学的系统研究。本研究旨在探讨中国人群中PESK的临床表型特点及其一致和差异性，并对其家系传递特点进行分析，同时采用测序的方法筛查某些候选致病基因的突变，以期为明确其分子发病机制提供新的线索。
本研究检索并收集国内自1980年以来报道的6个PSEK家系资料，分析和比较了不同家系间临床表型和传递模式，同时参考OMIM记载的分子遗传学信息选择了几个候选致病基因，并对其中一个家系中患者的这些基因进行了突变筛查。
对6个PSEK家系的临床表型及遗传资料进行比较分析结果显示：1)多数患者早年发病，表型至青春期发展充分；2)典型皮损为对称分布的散在红色斑块，表面出现角化和鳞屑，部分患者可出现特殊表型；3)本病在家系中的传递基本均呈连续性，成员发病无显著性别差异，同胞中患者比例接近1／2；4)患者群体中绝大部分临床表型充分表现，但外显率并非100％。
对其中一个PSEK家系进行的候选致病基因突变筛查结果显示：1)Loricin基因未发生突变；2)EKV相关致病基因GJB3和GJB4也未见突变发生。
本研究结果表明：1)中国人PSEK的临床表型谱及遗传特点与其他人群无显著差异；2)本病外显率高，但不同患者临床表型之间存在差异表达；3)本病存在遗传异质性，很可能存在其他致病基因，值得进一步进行研究。
The term erythrokeratoderma (EK) means a heterogeneous group of disorders characterized by the mixture of erythematous and hyperkeratotic lesions by dissimilar mode; two major clinical subtypes have been described as erymrokeratodermia variabilis and progressive symmetric erythrokeratodermia. Both of them are autosomal dominant diseases with incomplete penetrance and variable expression and their molecular mechanism are unknown. Ishida-Yamamoto have acomplished serial study on PSEK, but his results had received suspicion from other researchers. To explore the penotype features, inheritance mode and molecular mechanism of PSEK patients in China, we analyzed the clinical features of 6 Chinese PSEK pedigrees which have been published since 1980 and performed mutation detection in some candidate genes by direct sequencing.
The results about penotype shows: (1)most patients occurs during the first year or childhood, and the illness state fully develops in adulthood; (2)the typical lesion is hyperkeratotic erythematous with small scales, and some patients have distinguishing penotypes; (3)the disease transfer continuously in pedigrees, patients have no difference in gender and disease affect about half member in brethren; (4)clinical penotypes of most patients fully express but penetrance is not 100%.
The results of mutation detection show there are no mutations on Loricrin gene and candidate genes of EKV (GJB3 and GJB4) .
We concluded: (1)the penotype spectrum and inheritance feature of Chinese PSEK are similar with other ethnic group; (2)PSEK in Chinese group also shows high penetrance and variable expressivity; (3)the genetic mechanism of PSEK may exist mutation heterogeneity, or there are other genes take part in its pathogenesis, and more investigation are needed in discovery of the molecular mechanism of PSEK.
引文
1. Nir M,Tanzer F. Progressive symmetric erythrokeratodermia. Dermatologica. 1978, 156:268-273
2. Gray LC, Davis LS, Guill MA. Progressive symmetric erythrokeratodermia. J Am Acad Dermatol. 1996, 34:858-859
3. Stevens HP, KelsellDP, Bryant SP, Bishop DT, Spurr NK, Weissenbach J,Marger D, et al. Linkage of an American pedigree with palmoplantar keratoderma and malignancy to 17q24: literature survey and proposed updated classification of the keratodermas. Arch Dermatol. 1996, 132:640-651
4. Christiano AM. Frontiers in keratodermas: pushing the envelope. Trends Genet. 1997, 13:227-233
5. Mendes da Costa S. Erythrokeratodermia variabilis in a mother and daughter. Acta Derm Venereol (Stockh). 1925, 6: 255-261.
6. MacFarlane AW, Chapman SJ, Verbov JL. Is erythrokeratoderma one disorder? A clinical and ultrastructural study of two siblings. Br J Dermatol. 1991, 124: 487-491.
7. Brown J, Kierland RR. Erythrokeratodermia variabilis:report of three cases and review of the literature. Arch Derport. matol. 1966, 93:194-201
8. Hopsu-Havu VK, Tuohimata P. Erythrokeratodermia congenitalis progressiva symmetrica : an analysis of kinetics of epidermal cell proliferation. Dermatologica. 1971, 142:137-144
9. Ishida-Yamamoto A, McGrath JA, Lam H, Iizuka H, Friedman RA, Christiano AM. The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the comified cell envelope. Am J Hum Genet. 1997, 61 : 581-589
10. MacFarlane AW, Chapman SJ, Verbov JL. Is erythrokeratoderma one disorder? a
clinical and ultrastructural study of two siblings. Br J Dermatol. 1991,124:487-491
11. Noordhoek FJ: Over erythro-et keratodermia variabilis. Thesis: Utrecht (pub.)1950. Note: Cited by Schnyder VW and Klunker W: Erbliche Verhornungsstoerungen der Haut. In Gottron HA and Schnyder VW: Vererbung von Hautkrankheiten. Berlin: Springer-Verlag, 1966
12. van der Schroeff JG, Nijenhuis LE, Meera Khan P, Bemini LF, Schreuder, GMT,van Loghem E, Volkers WS, Went LN. Genetic linkage between erythrokeratodermia variabilis and Rh locus. Hum Genet. 1984, 68:165-168
13. van der Schroeff JG, van Leeuwen-Comelisse I, van Haeringen A, Went LN. Further evidence for localization of the gene of erythrokeratodermia variabilis. Hum Genet. 1988, 80:97-98
14. Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH, DiGiovanna JJ,Compton JG, Bale SJ. Mutations in the human cormexin gene GJB3 cause erythrokeratodermia variabilis. Nature Genet. 1988, 20: 366-369
15. Macari F, Landau M, Cousin P, Mevorah B, Brenner S, Panizzon R, Schorderet D. F, Hohl D, Huber M. Mutation in the gene for cormexin 30. 3 in a family with erythrokeratodermia variabilis. Am J Hum Genet. 2000, 67:1296-1301
16. Suga Y, Jarnik M, Attar PS, Longley MA, Bundman D, StevenAC, Koch PJ,Roop DR. Transgenic mice expressing a mutant form of loricrin reveal the molecular basis of the skin diseases, Vohwinkel syndrome and progressive symmetric erythrokeratoderma. J CellBiol. 2000, 151 (2): 401-412
17. Richard G, Brown N, Rouan F, et al. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 Cx30.3 and genotype—phenotype correlations. J Invest Dermatol. 2003; 120:601-609
18. Richard G, Brown N, Smith LE, TerrinoniA, MelinoG, MackieRM, Bale SJ,Uitto J. The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3. Hum Genet. 2000 Mar: 106 (3): 321-329
19．娄卫海，周冬梅，周垒，邓丙戌．进行性对称性红斑角皮症1例及家系调查．临床皮肤科杂志．2003，32：31-32
20．姚春华．进行性对称性红斑角化症3例报告．中华皮肤科杂志．1984，17：129-130
21．张风翔．进行性对称性红斑角化病4代7例报道．中华皮肤科杂志．1985，18：188
22．汪新义，张基瑞，陈树民，卢宪梅．进行性对称性红斑角化病一家族报告．中华皮肤科杂志．1995，28：337-338
23. Yoneda A, Honl D, McBride OW, Wang M, Cehrs KU, Idler WW, Steinert PM. The human Ioricrin gene. J Biol Chem. 1992, 267:18060-18066
24. VolzA, Korge BP, Compton JG, Ziegler A, Steinert PM, Mischke D. Physical mapping of a functional cluster of epidermal differentiation genes on chromosome lq21. Genomics. 1993, 18:92-99
25. Candi E, Melino G, Mei G, Tarcsa E, Chung SI, Marekov LN, Steinert PM. Biochemical, structural and transglutaminase substrate properties of human loricrin, the major epidermal comified cell envelope protein. J Biol Chem. 1995, 270:26382-26390
26. Wilgoss A, Leigh IM,. Barnes MR, et al. Identication of a novel mutation R42P in the gap junction protein b3 associated with autosomal dominant erythrokeratoderma variabilis. J Invest Dermatol. 1999, 113:1119-1122
27. Gottfried I, Landau M, Glaser F, et al. A mutation in GJ-B3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective tracking of the connexin 31 protein. Hum Mol Genet. 2002, 11:1311-1316