先天性厚甲症Ⅱ型一家系角蛋白17基因突变的研究

目的 研究一先天性厚甲症Ⅱ型(PC-Ⅱ)患者家系基因突变,探讨基因突变和临床表现的关系.方法 PCR扩增外周血基因组DNAK17基因第一外显子，PCR产物进行序列分析。结果 家系中3例患者（2例为迟发型厚甲，分别在4岁和15-16岁发生）K17基因第92位密码子由AAT突变为AGT，导致K17角蛋白1A区N92S突变，而该家系中的2例正常人及与该家系无关的50例正常人未发现此突变。结论 该PC-Ⅱ型家系存在K171A区N92S突变，K171A区突变可呈现为迟发型先天性厚甲。角蛋白基因突变位置可能不是PC-Ⅱ厚甲发生年龄的唯一决定因素，可能还存在其它遗传或环境因素决定PC-Ⅱ厚甲发生的年龄。     

先天性厚甲症遗传学研究进展

先天性厚甲症是一种罕见的遗传性外胚叶缺陷性疾病。临床上分为两种类型,主要表现为指(趾)甲的过度角化增厚及其他外胚叶缺陷,均与角蛋白异常有关。本文就先天性厚甲症的临床分型、致病基因的结构和功能、动物模型的构建及基因治疗等方面进行综述。     

先天性厚甲症2家系中角蛋白16和17的基因突变

目的了解先天性厚甲症Ⅰ型(PC-Ⅰ)及Ⅱ型(PC-Ⅱ)患者家系的基因突变。探讨其基因突变和临床表现的关系。方法扩增外周血基因组DNA中角蛋白16基因的第1~6外显子及K17基因的第1外显子,对PCR产物进行序列分析。结果PC-Ⅰ家系(家系1)中患者K16基因第127位密码子由CGC突变CCC,导致K16角蛋白1A区的精氨酸由脯氨酸替代(R127P);PC-Ⅱ家系(家系2)中2例患者K17基因第99位密码子由CTG突变为CCG,导致K17角蛋白1A区的亮氨酸由脯氨酸替代(L99P),而这两个家系中的正常人及与此两家系无关的50例正常人未发现此突变。结论该PC-Ⅰ家系存在角蛋白16的R127P突变,PC-Ⅱ家系存在角蛋白17的L99P突变。3例厚甲症患者检测到的2个角蛋白突变均由K16及K17发生错义突变,导致其编码的相应氨基酸由脯氨酸替代。此类突变可引发较重的临床表现,即呈现典型PC-Ⅰ型或PC-Ⅱ型,不会呈现其他较轻的临床亚型。     

伴皮角样损害的先天性厚甲症

报告1例伴有皮角样损害的先天性厚甲症.患者男,17岁.因指、趾甲增厚伴全身出现泛发皮角样改变就诊.患者自3岁起逐渐出现20甲变黄、增厚、分离,伴发严重掌跖角化,以及多发性皮角样损害.患者角蛋白基因KRT6A、KRT6B、KRT16、KRT17以及连接蛋白基因GJB6编码区的全部外显子及其侧翼序列均未检测到致病性突变.     

Ⅱ型先天性厚甲症一家系KRT基因突变检测

目的:检测先天性厚甲症一家系中KRT6b和KRT17基因突变位点。方法:提取先证者、其父母(母亲为患者,父亲正常人)及100名正常对照者外周静脉血DNA,PCR技术扩增KRT6b和KRT17基因编码序列,Sanger测序法对PCR扩增产物进行测序。结果:先症者及其母亲在KRT17基因1号外显子上存在错义突变(c.275AG),KRT6b基因不存在任何突变。先证者父亲及100名正常对照者中未检测到任何突变。结论:此家系患者是由于KRT17基因突变(c.275AG,p.Asn92Ser)所致。     

先天性厚甲症基因研究进展

先天性厚甲综合征近几年的研究有较大进展 ,尤其是发病机理 ,不断有新的突变位点被发现 ,除了常见的热点突变区外 ,还有其它位点。本文综述了临床各型的基因突变位点及基因的诊断与防治 ,以对本病的基因研究有所了解。     

一先天性秃发家系HR和CDSN基因突变的筛查

目的：对山东省一5代30人的先天性秃发家系进行HR、CDSN基因的突变筛查，以期寻找致病基因。方法：收集家系成员的临床资料及血液样本，抽提外周血基因组DNA，进行PCR扩增，采用虾碱性磷酸酶及核酸外切酶对扩增产物进行纯化，然后用ABI PRISM 3700自动测序仪进行测序，最后用Autoassembler软件与基因组序列对比，查找有无突变。结果：未发现突变。但找到12个多态位点，其中11个是首次发现，结论：HR、CDSN基因可能与本先天性秃发家系无关。     

先天性厚甲症I型一家系K6a基因突变检测

目的：研究先天性厚甲症I型（Pachyonychia congenitatype1,PC-1）一家系K6a基因突变。方法：提取PC-1患者和100名正常对照的外周血白细胞基因组DNA,采取长片段聚合酶链反应（PCR）扩增基因的全部编码序列,然后以产物为模板,采用巢式PCR扩增突变热点区,最后通过DNA直接测序确定基因突变位点和类型。结果：DNA测序发现患者K6a基因第1403位核甘酸由胸腺嘧啶（T）变为腺嘌呤（A）,导致K6a的2B螺旋区末端第468位密码子由亮氨酸（L）变为谷氨酰胺（Q）。而该家系中的正常人及100名正常对照均未发现此突变。结论：该患者存在角蛋白K6aIA68Q突变,进一步证明了螺旋边界序列是角蛋白K6a基因的突变热点区。     

先天性厚甲征Ⅱ型一家系6例

先证者男,22岁。自幼指(趾)甲增厚,呈褐色。10年前颈部出现粟粒大小丘疹,8年前颈部出现同样皮疹,6年前双手中指、无名指、小指的指甲变薄,后又增厚,5年前全身出现大小不等浅白色丘疹、结节,质硬,逐渐增大。诊断:先天性厚甲征Ⅱ型。     

先天性厚甲症

先天性厚甲症是一罕见的遗传性胚叶缺陷性疾病，主要表现为甲过度角化和营养不良，掌跖角化、多汗，毛囊角化及粘膜白斑和多发性脂囊瘤等。发病机制至今尚未完全清楚。现就先天性厚甲症的分型、临床表现、组织学改变和治疗等作简要综述。     

Novel keratin 17 mutations in pachyonychia congenita type 2

Pachyonychia congenita type 2 is an inherited ectodermal dysplasia characterized by hypertrophic nail dystrophy and multiple pilosebaceous cysts. Focal nonepidermolytic palmoplantar keratoderma, natal teeth, and pili torti may also be present. Epithelial tissues affected in pachyonychia congenita type 2 express the keratin pair K6b/K17. Here, we report three novel heterozygous mutations in the K17 gene (KRT17A) in patients presenting with pachyonychia congenita type 2. These mutations, R94-98del (deletion of the peptide sequence RLASY) and missense mutations R94P and L95Q, are all within the 1A domain hotspot for pathogenic keratin mutations.     

Increased pachyonychia congenita severity in patients with concurrent keratin and filaggrin mutations

Pachyonychia congenita (PC), a rare autosomal‐dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16 or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Loss‐of‐function mutations in the filaggrin (FLG) gene underlie the most prevalent skin disorder of cornification, ichthyosis vulgaris (IV), which presents with generalized scaling and is also associated with atopic dermatitis. Recently, FLG mutations have been reported to increase phenotype severity of X‐linked ichthyosis and alopecia areata. We report a parent–child trio in which the mother and the son have PC and the father has IV. Both the mother and the son are carriers for the KRT16 mutation p.Leu132Pro. The son, who is much more severely affected than his mother, in addition carries the heterozygous FLG mutation p.R2447X, which was inherited from the father. This observation suggests that coinheritance of mutations in KRT16 and FLG may aggravate the PC phenotype and that FLG could serve as a genetic modifier in PC.     

Mutation report: identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2

Pachyonychia congenita type 2 (PC-2), also known as Jackson-Lawler type PC, is an autosomal dominant disorder characterized by hypertrophic nail dystrophy associated with focal keratoderma and multiple pilosebaceous cysts. It has been demonstrated that PC-2 is associated with germline mutations in the keratin 17 (K17) gene and in its expression partner keratin 6b. In this report, we describe a novel germline mutation in K17, M88T, in a family with PC-2.     

Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1

The peripheral benzodiazepine receptor (PBR) is a protein of mitochondrial outer membranes utilizing porphyrins as endogenous ligands. PBR is part of a heteromeric receptor complex involved in the formation of mitochondrial permeability transition pores and in the early events of apoptosis. PBR may function as an oxygen-dependent signal generator; recent data indicate that these receptors may preserve the mitochondria of haematopoietic cell lines from damage caused by oxygen radicals. To identify PBRs in human skin, we used a specific monoclonal antibody directed against the C-terminus fragment of the human receptor. PBR immunoreactivity was found in keratinocytes, Langerhans cells, hair follicles and dermal vascular endothelial cells. Interestingly, confocal microscopic examination of skin sections revealed that PBR expression was strongly upregulated in the superficial differentiated layers of the epidermis. Ultrastructurally, PBRs were distributed throughout the cytoplasm but were selectively expressed on the mitochondrial membranes of epidermal cells. The elevated level of PBRs in the spinous layer was not associated with an increased number of mitochondria nor with an increased amount of mRNA as assessed by in situ hybridization on microautoradiographed skin sections. The present work provides, for the first time, evidence of PBR immunoreactivity in human skin. This mitochondrial receptor may modulate apoptosis in the epidermis; its increased expression in differentiated epidermal layers may represent a novel mechanism of natural skin protection against free radical damage generated by ultraviolet exposure.