一家族性毛发上皮瘤家系CYLD1基因突变的研究

目的:收集山东一多发性家族性毛发上皮瘤家系,通过直接测序法检测该家系圆柱瘤病肿瘤抑制基因(cylindromatosis tumor-suppressor gene,CYLD1)第16、18号外显子是否存在突变。方法:提取家系成员外周血基因组DNA,利用PCR特异性扩增、直接测序方法对CYLD1基因的第16、18号外显子进行检测。结果:本家系成员的CYLD1基因第16、18号外显子未发现突变。结论:未发现本家族性毛发上皮瘤家系CYLD1基因第16、18号外显子存在突变,提示家族性毛发上皮瘤具有遗传异质性。     

家族性原发性皮肤淀粉样变遗传学分析

目的 探讨家族性原发性皮肤淀粉样变(FPCA)与染色体1q21.3-24.2和5p13.1-q11.2的连锁关系.方法 在染色体1q21.3-24.2和5p13.1-q11.2处选取16个微卫星标记位点,用Linkage软件计算各位点连锁概率.结果 所有位点连锁分析所得的LOD值均<-2,排除了连锁关系.结论 该家系的易感基因不在染色体1q21.3-24.2和5p13.1-q11.2区域,FPCA存在遗传异质性.     

多发性家族性毛发上皮瘤1家系CYLD基因突变的检测

目的检测一个中国汉族多发性家族性毛发上皮瘤(multiple familial trichoepithelioma,MFT)家系的CYLD基因突变情况,初步探讨该疾病发生与突变位点的相关性。方法采用聚合酶链反应扩增家系患者和健康个体CYLD基因的全部外显子,并进行DNA测序,以100例无亲缘关系的正常人作为对照。结果该家系2例患者CYLD基因的17号外显子均检测到杂合无义突变c.2272CT,导致第758位精氨酸被终止密码子替代(R758X)。结论 CYLD基因无义突变c.2272CT可导致编码蛋白的结构与功能改变,是本家系的发病基础。     

原发性皮肤淀粉样变一家系致病基因的连锁分析

目的: 探讨家族性原发性皮肤淀粉样变(FPCA)致病基因与染色体1q23,5p13.1-q11.2以及10号染色体近着丝粒区的连锁关系.方法: 采用10个荧光微卫星标记对一FPCA家系进行连锁分析,在染色体1q23,5p13.1-q11.2以及10号染色体近着丝粒区选择10个荧光微卫星标记.通过Linkage5.1软件包计算连锁概率.结果: 各位点连锁分析所得的LOD值均小于-2,显示该家系致病基因与这10个位点均不连锁.结论: FPCA存在遗传异质性,该家系的致病基因可能在其他新的基因位点上.     

多发性家族性毛发上皮瘤致病基因的研究进展

多发性家族性毛发上皮瘤是一种常染色体显性遗传的皮肤附属器肿瘤,临床较少见。通常20岁前发病,女性患病率高于男性。此肿瘤具有遗传异质性,不同人种致病基因可能位于不同染色体上。从多发性家族性毛发上皮瘤致病基因的定位、克隆、突变检测、功能与结构的研究叙述。     

多发性家族性毛发上皮瘤致病基因的研究进展

多发性家族性毛发上皮瘤是一种常染色体显性遗传的皮肤附属器肿瘤，临床较少见。通常20岁前发病，女性患病率高于男性。此肿瘤具有遗传异质性，不同人种致病基因可能位于不同染色体上。从多发性家族性毛发上皮瘤致病基因的定位、克隆、突变检测、功能与结构的研究叙述。     

几种遗传性色素性疾病临床与分子遗传学研究进展

几种以常染色体显性遗传方式为主的遗传性色素性疾病在临床表现和分子遗传学方面研究取得重要进展,包括屈侧网状色素异常、遗传性泛发性色素异常症、家族性进行性色素沉着症以及家族性进行性色素沉着和色素减退症。屈侧网状色素异常由KRT5基因（12q13．13）功能丧失性突变所致;SASH1（6q24．2-q25．2）、ABCB6基因（2q33．3-q36．1）突变与常染色体显性遗传性泛发性色素异常症发病有关,而常隐类型致病基因定位于12q21-q23;家族性进行性色素沉着症由KITLG基因（12q21．12-q22）或19p13．1-pter区域内基因突变所致。家族性进行性色素沉着和色素减退症的发病与KITLG基因突变有关。以上基因突变主要通过影响黑素降解、黑素细胞迁移、黑素合成或黑素母细胞增殖等引起皮肤色素沉着异常。     

播散性浅表光线性汗孔角化病致病基因的定位

目的 对播散性浅表光线性汗孔角化病(DSAP)的致病基因进行定位。方法 收集一个DSAP家系成员的血样抽提基因组DNA,选用12号染色体长臂上已知致病区域的7个微卫星标记进行基因扫描,并用LINKAGE软件(5.1Version)对基因分型结果进行连锁分析。结果 连锁分析结果发现本家系在微卫星标记D12S79的两点最大LOD值为5.15(θ=0.00)。结论 DSAP致病基因位于12号染色体的长臂上。     

6号染色体上可能存在银屑病易感基因

目的 研究中国人寻常型银屑病与6p21.3区域内的六个微卫星标记和4q上的两个微卫星标记是否连锁,以寻找银屑病易感基因位点。方法 利用选取的微卫星位点作为标记,采用微卫星荧光标记-基因扫描及分型技术,选取205例经确诊并符合寻常型银屑病诊断标准的患者,对其中14个银屑病家系进行连锁分析。结果 在研究的家系中未发现4q上的微卫星标记与银屑病易感基因之间的连锁,而在染色体6p21.3区域存在着与之有连锁关系的微卫星标记位点(在D6S273位点上两点分析最大LOD值为1.26)。结论 本研究表明在中国人银屑病患者中,染色体6p21.3区域可能存在银屑病易感基因。     

遗传性秃发或少毛症研究进展

遗传性秃发或少毛症是皮肤科一组比较少见的疾病.根据临床类型不同其具有特征性的临床表现各异.该组疾病的遗传方式可表现为常染色体显性遗传、常染色体隐性遗传和X连锁显性或隐性遗传.在分子遗传学方面,已有多个致病基因位点和/或致病基因被确定,如8p21、6p21、18p11、16q22、18q12、3q26、1p21、Xq13、5q32等致病基因位点和HR、CDH3、CDSN、DSG4、LIPH、ATP7A等基因.     

A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome

Brooke-Spiegler syndrome (BSS, familial cylindromatosis or turban tumor syndrome) is an inherited disease characterized by neoplasms of the skin appendages such as cylindroma, trichoepithelioma, and spiradenoma. The disease has been mapped to 16q12-13, and mutations in the CYLD gene have been identified in families with this disorder. Of interest, multiple familial trichoepithelioma (MFT) has been described as a distinct disorder characterized by the familial occurrence of trichoepitheliomas. MFT has been mapped to 9p21; however, to date a candidate gene has not been identified. In this report, we describe a four-generation family with BSS presenting predominantly with trichoepitheliomas (resembling MFT phenotype). We identified a novel missense mutation in the CYLD gene, designated E474G, in the affected individuals of this family. Our findings exemplify clinical heterogeneity within BSS and extend the body of evidence that mutations in CYLD are implicated in this disease. Although not conclusive, these findings suggest that BSS and MFT may represent a single entity.     

Identification of the cylindromatosis tumor-suppressor gene responsible for multiple familial trichoepithelioma

Multiple familial trichoepithelioma (MFT) is an autosomal dominant skin disease characterized by the presence of many small benign tumors with pilar differentiation predominantly on the face. The first locus has been previously mapped to chromosome 9p21, but no gene for MFT has been identified to date. To identify the disease gene in a large Chinese family, we initially performed linkage analysis with microsatellite markers from 9p21, but failed to confirm the linkage to this region. Previous publications showed MFT and familial cylindromatosis (FC) can occur within one family and in a single person. Therefore, we speculated that the cylindromatosis gene (CYLDI gene) responsible for FC may be related to the pathogenesis of MFT. In view of that, we genotyped all available individuals using 11 microsatellite markers spanning the CYLDI gene region at 16q12-q13. We identified the linkage of MFT to this region. Mutation analysis in the CYLDI gene detected a frameshift mutation, designated as c.2355-2358delCAGA. The study firstly identified the cylindromatosis gene responsible for MFT and showed that different mutations of the CYLDI gene can give rise to distinct clinical and histological expression such as FC and MFT.     

A novel mutation of CYLD in a Chinese family with multiple familial trichoepithelioma

Background Trichoepithelioma is a benign cutaneous tumour that originates from hair follicles and occurs either as a sporadic non-familial or a multiple-familial type. Recently, several mutations in the cylindromatosis (CYLD) gene have been reported in multiple familial trichoepithelioma (MFT). Objectives To report a Chinese family of MFT and to explore the genetic mutation. Methods A Chinese pedigree of typical MFT was subjected to mutation detection in CYLD. Direct sequencing of all PCR products of the whole coding regions of CYLD gene was performed to identify the mutation. Results The c.1178-1179delCA (p.T393fs) mutation was found in CYLD gene in the affected members, but not in the healthy individuals in the family. Conclusion Our study found a novel mutation in exon 10 of CYLD gene.     

Multiple (familial) trichoepitheliomas: a clinicopathological and molecular biological study, including CYLD and PTCH gene analysis, of a series of 16 patients

Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.     

Case of the Brooke-Spiegler syndrome

A 36-year-old woman presented with lesions on her scalp, face and trunk. Histopathological examination of these lesions demonstrated facial trichoepithelioma, and scalp cylindroma. A solitary nodule on the trunk had features of cylindroma, spiradenoma and trichoepithelioma, a previously unreported occurrence. Based on the clinical picture, the diagnosis of Brooke-Spiegler syndrome was established. Genetic studies confirmed the diagnosis, demonstrating a splice site mutation, designated 1518+2T>C, on the CYLD1 gene of chromosome 16q12-q13.     

Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity

Brooke-Spiegler syndrome, familial cylindromatosis, and familial trichoepithelioma are autosomal-dominant genetic predispositions for benign tumors of skin appendages caused by mutations in the CYLD gene localized on chromosome 16q12-q13. The encoded protein functions as ubiquitin-specific protease (UBP), which negatively regulates NF-kappaB and c-Jun N-terminal kinase (JNK) signaling. We investigated five families affected with these skin neoplasms and identified four premature stop codons and the novel missense mutation D681G in a family in which 11 of 12 investigated tumors were trichoepitheliomas. CYLD protein harboring this missense mutation had a significant reduced ability to inhibit TNF receptor-associated factor (TRAF)2- and TRAF6-mediated NF-kappaB activation, tumor necrosis factor-alpha (TNFalpha)-induced JNK signaling, and to deubiquitinate TRAF2. CYLD-D681G was coimmunoprecipitated by TRAF2, but was unable to cleave K63-linked polyubiquitin chains. Aspartic acid 681 is highly conserved in CYLD homologues and other members of the UBP family, but does not belong to the Cys and His boxes providing the CYLD catalytic triad (Cys601, His871, and Asp889). As reported previously, the homologous residue D295 of HAUSP/USP-7 forms a hydrogen bond with the C-terminal end of ubiquitin and is important for the enzymatic activity. These results underline that D681 in CYLD is required for cleavage of K63-linked polyubiquitin chains.     

Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation

Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT), originally described as distinct entities, share overlapping clinical findings. Patients with BSS are predisposed to multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. FC, however, is characterized by cylindromas and MFT by trichoepitheliomas as the only tumor type. These disorders have recently been associated with mutations in the CYLD gene. In this report, we describe three families with BSS, one with FC, and two with MFT phenotypes associated with novel and recurrent mutations in CYLD. We provide evidence that these disorders represent phenotypic variation of a single entity and lack genotype-phenotype correlation.     

Evidence for two susceptibility loci on chromosomes 22q12 and 6p21-p22 in Chinese generalized vitiligo families

Vitiligo is an acquired depigmentation disorder of the skin and hair caused by the selective destruction of melanocytes from the epidermis that gives rise to well-defined depigmented patches. Strong genetic predisposition has been well recognized. Previous reports have described five significant vitiligo susceptibility loci spread over five different chromosomes, 1p31 (AIS1), 7q (AIS2), 8p (AIS3), 4q13-q21 (AIS4), and 17p (SLEV1). In addition, our previous genome-wide scan of 106 Chinese vitiligo families presented suggestive linkages on five additional chromosome segments, 1p36, 6p21-p22, 6q24-q25, 14q12-q13, and 22q12. To clarify the significance of these suggestive loci, we have now extended this study to a total of 143 Chinese vitiligo families and increased the marker density. Two linkage signals on 6p21-p22 and 22q12 that were previously only suggestive now meet genome-wide criteria for significant linkage, establishing their importance as major vitiligo susceptibility loci. Linkage signals on 1p36 and 6q24-q25 did not improve our previous findings, but on 14q showed negative in the 143 family cohorts. The results presented here further demonstrate the genetic complexity of vitiligo pathogenesis and point to new chromosomal locations for further research to identify the specific genes involved in this process.