两个X连锁鱼鳞病家系中类固醇硫酸酯酶基因缺失

检测2个中国X连锁鱼鳞病家系中的基因突变。用PCR方法扩增类固醇硫酸酯酶(STS)基因的10个外显子，并对扩增产物进行测序。第一个家系中先证者的STS基因6、7外显子缺失，第二个家系先证者的整个STS基凶缺失。本研究明确了这两个家系中的基因突变，从而为这两个家系的后代进行产前诊断提供了可能。     

X性联锁遗传鱼鳞病一家系的STS基因研究

目的 研究一 X性联锁遗传鱼鳞病(XLI)家系基因突变,探讨基因突变与临床表现的关系,为进一步开展基因诊断和基因治疗奠定基础。方法 应用PCR方法扩增家系中的先证者及其母亲及与该家系无关的50例正常人外周血基因组DNA STS基因的第一外显子和第十外显子。以角蛋白hHb6为引物,作内对照。结果 家系中先证者的STS基因全部缺失,而先证者之母和与该家系无关的50例正常人未发现缺失。先证者及先证者之母的内对照引物PCR扩增后都有产物。结论 该XLI家系存在STS基因缺失,该缺失引发出XLI特有的皮肤病变。     

遗传性皮肤病

20 0 5 0 1 41　X性联锁遗传鱼鳞病一家系的STS基因研究 /刘安 (西安交大二院皮肤科 )…∥中国皮肤性病学杂志 . 2 0 0 4,1 8(7) . 40 3～ 40 5用PCR方法扩增一家系中先证者和其母亲及与该家系无关的 5 0例正常人外周血基因组DNASTS基因的第 1外显子和第 1 0外显子。结果先证者的STS基因全部缺失 ,其母及 5 0例正常人未发现缺失 ,先证者及其母亲的内对照引物PCR扩增后都有产物。认为这一X性联锁遗传鱼鳞病 (XLI)家系存在STS基因缺失 ,该缺失引发出XLI特有的皮肤病变。图 3参 1 1　 (汤亚娥 )2 0 0 5 0 1 42　板层状鱼鳞病患者谷…     

X-性联锁遗传鱼鳞病一家系STS基因研究

研究X-性联锁遗传鱼鳞病(XLI)一家系基因突变情况,检测基因突变与临床表现的关系,为进一步开展基因诊断和基因治疗奠定基础.抽取该家系中患者、正常人及与这些家系无关的100例正常人的外周血,提取外周血基因组DNA.应用PCR方法扩增外周血基因组DNA类固醇硫酸酯酶(STS)基因的第1、2和10外显子.结果:该家系中的患者STS基因全部缺失,家系中正常人和与该家系无关的100例正常人未发现这种缺失.该缺失引发出XLI特有的皮肤病变.     

X-性连锁鱼鳞病一家系类固醇硫酸酯酶基因研究

目的 检测一个中国汉族人X-性连锁鱼鳞病家系的类固醇硫酸酯酶(STS)基因突变情况.方法 收集1个X-性连锁鱼鳞病家系的临床资料,提取外周血DNA,通过PCR扩增外周血基因组DNA类固醇硫酸酯酶基因的第1和第10外显子,以表型正常家系成员及50例健康人为正常对照.结果 家系内全部患者均存在STS基因的完全缺失,即10个外显子均缺失,家系中正常人及对照者未发现上述缺失.结论 STS基因的完全缺失可能为导致该家系临床表型的主要原因.

Abstract：

Objective To detect the steroid sulfatase (STS) gene mutation in a Chinese pedigree with X-linked ichthyosis (XLI). Methods Genomic DNA was extracted from the peripheral blood of 3 affected patients and unaffected members in this family and 50 unrelated healthy volunteers followed by the amplification of the exon 1 and exon 10 of STS gene by PCR. Results Complete deletion of the exon 1 to 10 of STS gene was detected in all the patients in this pedigree with XLI, while no mutation was found in this gene in unaffected members of this family or normal human controls. Conclusion The complete deletion of STS gene is likely to be the main cause of the phenotype of XLI in this family.     

X连锁鱼鳞病并发Meleda角化病一例临床特征及SLURP-1和STS基因突变分析

目的 报道1例X连锁鱼鳞病并发Meleda角化病,并检测其基因突变.方法 收集临床资料,提取患儿及其父母外周血基因组DNA,PCR扩增SLURP-1和STS基因全部外显子及其侧翼序列,以100例健康人作为对照,对扩增产物行琼脂糖凝胶电泳检测,并对SLURP-1基因扩增产物进行DNA测序.结果 患儿躯干、四肢泛发规则排列的棕褐色或黑色多角形鳞屑,掌跖、肘膝、腹股沟、肛周红斑,过度角化,向背侧延伸,诊断为X连锁鱼鳞病并发Meleda角化病.基因检测提示,STS全基因缺失;SLURP-1基因第3外显子第286位核苷酸发生C→T纯合突变(c.286C＞T),导致其编码蛋白质在第96位氨基酸出现终止改变(p.R96*),其父母均为c.286C＞T杂合突变携带者.健康对照未发现此突变.结论 该患者携带STS全基因缺失和SLURP-1基因纯合无义突变,可能是导致X连锁鱼鳞病并发Meleda角化病的原因.     

X连锁隐性鱼鳞病基因型表型分析

目的:分析4例X连锁隐性遗传性鱼鳞病(X-linked ichthyosis, XLI)患者的临床表现及遗传变异。方法:从中国汉族人群收集XLI患者，记录临床特征及家系信息，通过全外显子组测序分析患者基因上的单核苷酸变异(SNV)、插入和缺失(INDEL)及拷贝数变异(CNV)。结果:共收集4例XLI患者，均检测到STS基因缺失。其中1例患者同时伴有一个已报道的FLG基因无义突变：c.5368C>T(p.Gln1790Ter),该患者表现类似表皮松解性鱼鳞病症状。结论:XLI临床表现差异较大，全外显子组测序是一种诊断XLI的有效方法。携带FLG基因突变的XLI患者倾向于更重的临床表现。     

常染色体隐性遗传性鱼鳞病一家系表型、基因型与皮损超微结构研究

目的 探讨常染色体隐性遗传性鱼鳞病家系临床表型、基因型及超微结构。方法 观察常染色体隐性遗传性鱼鳞病患者临床表现。用PCR扩增TGM1基因15个外显子及其邻近剪切位点,双向直接测序;取先证者背部皮损做透射电镜观察,记录电镜表现特征。结果 先证者临床表现介于板层状鱼鳞病及非大疱性鱼鳞病样红皮病之间,其弟弟为火棉胶婴儿。先证者、其弟及父亲3号外显子第551位碱基胞嘧啶（C）→胸腺嘧啶（T）,其编码的第143位氨基酸由精氨酸变为半胱氨酸（R143C）;先证者、其弟及母亲4号外显子第759位胞嘧啶（C）→胸腺嘧啶（T）,使第212位氨基酸由丝氨酸转变为苯丙氨酸（S212F）。电镜观察发现,先证者皮损不仅有Ⅱ型结构表现,也同时存在Ⅲ型结构特征。结论 该家系患者携带复合杂合突变,R143C属于热点区,S212F为新发现的位点。携带TGM1基因突变的先证者皮损电镜表现为Ⅱ型,但同时发现有Ⅲ型结构存在。     

Chanarin-Dorfman综合征一例国内首报

【摘要】 目的 检测1例以鱼鳞病伴肝功能异常为主要临床表现的家系基因突变情况,并明确其诊断。方法 收集先证者临床资料,采集先证者及其父母外周血,提取基因组DNA,对先证者进行遗传性皮肤病目标基因外显子测序,确定突变位点,在家系中对突变位点进行Sanger测序验证,并对先证者及其父母外周血涂片等辅助检查结果进行分析。结果 先证者全身皮肤干燥,下肢可见白色细小鳞屑,伴有转氨酶升高、双耳轻度感音神经性耳聋和脂肪肝。先证者外周血基因组DNA中编码CGI-58蛋白的ABHD5基因第6外显子存在纯合突变（c.933dupA）,导致氨基酸序列发生移码突变（p.R312Tfs*45）,其父亲、母亲该位点均为杂合突变,突变与疾病符合共分离。先证者外周血涂片发现中性粒细胞内含脂质空泡,即Jordan小体阳性。结论 先证者表现为鱼鳞病样皮损和肝功能异常,结合其ABHD5基因纯合突变和外周血涂片Jordan小体阳性,诊断为Chanarin-Dorfman综合征。     

类脂质蛋白沉积症两家系调查及ECM1基因突变检测

目的:检测类脂质蛋白沉积症二家系中细胞外基质蛋白(ECM1)基因突变位点。方法:提取1号家系先证者及其母亲,2号家系先证者、父母、配偶及儿子外周血DNA。PCR技术扩增ECM1基因编码序列,采用一代Sanger法对PCR扩增产物进行测序。结果:1号家系先证者在7号外显子发现已知突变(纯合突变c.960GA),其母亲为杂合携带者;2号家系先证者为遗传复合体,是上述突变位点的杂合携带者,此外在3号外显子上存在1个插入突变c.142insC。结论:类脂质蛋白沉积症存在遗传异质性。     

四种遗传性鱼鳞病基因型与临床表型的相关性分析

目的对四种鱼鳞病(寻常型鱼鳞病;X性-联鱼鳞病;板层状鱼鳞病;大疱性鱼鳞病)的致病基因进行精细定位,并分析其基因型与临床表型的关系。方法对四种鱼鳞病各1例患者进行临床表型分析以及外周血DNA直接测序检测鱼鳞病FLG基因、STS基因、TGM1基因和K1,K10角蛋白基因的突变位点。结果①寻常型鱼鳞病患者在FLG基因的外显子5的第278位有G-T突变,613位有G-A突变。②板层状鱼鳞病患者TGM1基因外显子3的第504位碱基有C-T突变,使第142位氨基酸由精氨酸(R)转变为半胱氨酸(C),即R142C错义突变;外显子7的第1122位碱基有C-T突变,使348位氨基酸由精氨酸(R)突变为终止密码(R348X),导致其编码的蛋白缺失了C端的470个氨基酸。③X-性联鱼鳞病患者STS基因完全缺失。④大疱性鱼鳞病患者外显子5的第242碱基存在A-C突变,外显子6的第599位碱基均存在A-G突变,导致K1蛋白第633位氨基酸由赖氨酸(Lys)变为精氨酸(Arg)。结论鱼鳞病患者临床表型的不同与致病基因的突变位点密切相关。     

Deletion of exons 1-5 of the STS gene causing X-linked ichthyosis

X-linked ichthyosis is an inherited disorder due to steroid sulfatase deficiency. It is clinically characterized by dark, adhesive, and regular scales of the skin. Most X-linked ichthyosis patients present large deletions of the STS gene and flanking markers; a minority show a point mutation or partial deletion of the STS gene. In this study we analyzed the STS gene in a family with simultaneous occurrence of X-linked ichthyosis and ichthyosis vulgaris. X-linked ichthyosis diagnosis was confirmed through steroid sulfatase assay in leukocytes using 7-[3H]-dehydroepiandrosterone sulfate as a substrate. Exons 1, 2, 5, and 6-10, and the 5' flanking markers DXS1130, DXS1139, and DXS996 of the STS gene were analyzed by polymerase chain reaction. X-linked ichthyosis patients of the family (n = 4 males) had undetectable levels of STS activity (0.00 pmol per mg protein per h). The DNA analysis showed that only exons 6-10 and the 5' flanking markers of the STS gene were present. We report the first partial deletion of the STS gene spanning exons 1-5 in X-linked ichthyosis patients.     

Exacerbation of X-linked ichthyosis phenotype in a female by inheritance of filaggrin and steroid sulfatase mutations

Background

X-linked ichthyosis (XLI) is a relatively common, recessive condition caused by mutations in the steroid sulfatase (STS) gene. Common loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and predispose individuals to atopic eczema.

Objective

To test the hypothesis that co-inheritance of FLG mutations can act as a genetic modifier in XLI.

Methods

An unusually severe XLI phenotype in addition to eczema and mild childhood asthma was investigated in a female Indian patient by fluorescent in situ hybridization (FISH) for the common STS gene deletion. Direct sequencing of the entire FLG gene was also performed.

Results

FISH analysis revealed that the proband was homozygous for the common STS genomic deletion mutation. Further investigation revealed a frame-shift mutation 3672del4 in the gene encoding filaggrin (FLG), leading to premature termination of profilaggrin translation. Interestingly, her father, who had a very typical mild presentation of XLI, did not carry this FLG mutation in addition to his STS deletion. Her mother was a heterozygous carrier of the FLG mutation and consistent with this, had mild symptoms of ichthyosis vulgaris; she was also a heterozygous carrier of the STS deletion.

Conclusion

This is the second reported case of the modifying effects of FLG null alleles on XLI and strengthens the hypothesis that filaggrin defects can synergize with STS deficiency to exacerbate the ichthyosis phenotype.     

新发MBTPS2基因突变致毛囊性鱼鳞病、秃发、畏光综合征一例

【摘要】 本文首次报道1例MBTPS2基因c.1165C>T突变致毛囊性鱼鳞病、秃发、畏光综合征。先证者主要临床表现为皮肤干燥、先天性无头发、毛囊角化性丘疹、畏光,伴癫痫,智力、运动发育落后。应用二代测序及一代测序验证显示,先证者和其母亲在MBTPS2基因第9外显子区域存在c.1165C>T（p.pro389Ser）突变。根据患儿临床表现和MBTPS2基因突变遗传学特点,确诊为毛囊性鱼鳞病、秃发、畏光综合征。     

X linked recessive ichthyosis: Current concepts

In the present review, we describe the most importantaspects of the X-linked ichthyosis(XLI) and make a compilation of the some historic details of the disease. The aim of the present study is an update of the XLI. Historical, clinical, epidemiological, and molecular aspects are described through the text. Recessive XLI is a relatively common genodermatosis affecting different ethnic groups. With a high spectrum of the clinical manifestations due to environmental factors, the disease has a genetic heterogeneity that goes from a point mutation to a large deletion involving several genes to produce a contiguous gene syndrome. Most XLI patients harbor complete STS gene deletion and flanked sequences; seven intragenic deletions and 14 point mutations with a complete loss of the steroid sulfatase activity have been reported worldwide. In this study, we review current knowledge about the disease.     

Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis

Mutations inactivating the STS gene cause X-linked ichthyosis (XLI), whereas null mutations in the FLG gene cause ichthyosis vulgaris. Two brothers presented with XLI. One had a typical fine scaling, and the other was much more severely affected. Both patients carried STS missense mutation T165I. Furthermore, the more severely affected patient also carried heterozygous FLG mutation R501X, which was absent from his mildly affected brother. These data suggest that disrupting epidermal differentiation via different pathways can increase phenotypic severity. Owing to the high population frequency of FLG mutations, filaggrin is a possible genetic modifier in other genodermatoses.     

Somatic and germinal mosaicism for the steroid sulfatase gene deletion in a steroid sulfatase deficiency carrier

Steroid sulfatase deficiency results in X-linked ichthyosis, an inborn error of metabolism in which the principal molecular defect is the complete deletion of the steroid sulfatase gene and flanking markers. Mosaicism for the steroid sulfatase gene has not yet been reported in X-linked ichthyosis. In this study we describe an X-linked ichthyosis patient with complete deletion of the steroid sulfatase gene and his mother with somatic and germinal mosaicism for this molecular defect. The family (X-linked ichthyosis patient, grandmother, mother, and sister) was analyzed through steroid sulfatase enzyme assay, polymerase chain reaction, DNA markers, and fluorescence in situ hybridization of the steroid sulfatase gene. Steroid sulfatase activity was undetectable in the X-linked ichthyosis patient, very low in the mother, and normal in the grandmother and sister. The X-linked ichthyosis patient showed a 2 Mb deletion of the steroid sulfatase gene and flanking regions from 5'DXS1139 to 3'DXF22S1. The mother showed one copy of the steroid sulfatase gene in 98.5% of oral cells and in 80% of leukocytes. The grandmother and sister showed two copies of the steroid sulfatase gene. The origin of the X chromosome with the deletion of the steroid sulfatase gene corresponded to the grandfather of the proband. We report the first case of somatic and germinal mosaicism of the steroid sulfatase gene in an X-linked ichthyosis carrier and propose DNA slippage as the most plausible mechanism in the genesis of this mosaicism.