KRT9基因突变所致表皮松解性掌跖角化病1例

报告KRT9基因突变所致表皮松解性掌跖角化病1例.患者男,中国籍,32岁,手足角化性斑块30余年.皮肤科检查:双侧掌跖面可见对称性弥漫性角化斑块,皮肤粗糙增厚,呈灰黄色.皮损组织病理:表皮明显角化过度,颗粒层棘层增厚,皮突延长,颗粒细胞变性,考虑掌跖角化病.基因全外显子组测序结果:KRT9基因外显子检测出c.487C＞...     

表皮松解性掌跖角皮症一家系KRT9基因新突变

目的:检测表皮松解性掌跖角皮症一家系患者角蛋白9(KRT9)基因突变。方法:收集家系成员的临床资料和血样,提取家系中4例患者和3名正常人及50名与本家系无关的正常对照外周血DNA,采用PCR技术扩增KRT9基因所有编码区并进行测序,分别检测家系中的突变情况。结果:该家系中所有患者均存在KRT9基因错义突变(c.484TC),导致第162位密码子由TCT(丝氨酸)转变为CCT(脯氨酸)(p.S162P),家系中3名正常个体和50名健康对照均未发现上述突变。结论:KRT9基因c.484TC错义突变是导致该家系发生表皮松解性掌跖角皮症的遗传基础。     

表皮松解性掌跖角化病一家系KRT9基因突变检测

目的：检测一表皮松解性掌跖角化病(epidermolytic palmoplantar keratoderma,EPPK)家系中患者及其家族成员的KRT9基因突变。方法：收集该EPPK家系先证者及其家族成员临床资料,提取他们及100例无亲缘关系的健康对照外周血DNA,PCR扩增KRT9基因编码区的全部外显子及其侧翼序列,对产物直接测序,同时进行突变点的功能预测。结果：该家系所有患者的KRT9基因1号外显子第482位碱基均发生错义突变c.482A>G(p.Asn161Ser)。家系中未患病者及100名正常对照中均未发现此突变。SIFT和Polyphen-2软件预测c.482A>G(p.Asn161Ser)突变为有害变异位点。结论：KRT9基因的突变c.482A>G(p.Asn161Ser)可能是导致该家系发生表皮松解性掌跖角化病的原因。     

表皮松解性掌跖角化病一家系KRT9基因突变检测及生物信息学分析

目的:检测表皮松解性掌跖角化病1家系KRT9基因突变情况并进行生物信息学分析。方法:提取家系患者、正常人及100名健康志愿者外周血DNA,采用聚合酶链式反应(PCR)扩增KRT9基因全部外显子并测序。与数据库比对测序结果,运用生物信息学软件进行突变型蛋白质结构及功能预测分析。结果:患者KRT9基因1号外显子内检测到一处c.487CT错义突变(p.163RW),家族未患病成员以及100名正常对照中未发现突变。生物信息学分析提示该突变会导致蛋白质二级结构和理化性质改变,功能分析提示该突变会改变蛋白质生物功能。结论:本家系检测到1个KRT9基因的热点突变,该突变对于疾病发生发展可能具有较大作用。     

以严重掌跖角化过度为主要表现的表皮松解性角化过度症一家系报告及基因突变分析

目的:报告一个以严重掌跖角化过度为主要表现的表皮松解性角化过度症(epidermolytic hyperkeratosis,EHK)家系,并检测其基因突变情况.方法:收集1个EHK家系的临床资料,取先证者皮损行组织病理检查.提取先证者及其亲属外周血DNA,应用PCR扩增角蛋白1(KRTl)、角蛋白10(KRT10)和角蛋白9(KRT9)基因编码区的全部外显子及其侧翼序列并行双向DNA测序,以100名健康志愿者外周血DNA作正常对照.结果:先证者皮损组织病理符合表皮松解性角化过度,所有患者的KRT1基因第1436位碱基发生T→C错义突变,导致其第479位氨基酸从异亮氨酸(Ⅰ)变为苏氨酸(T) (p.I479T).家系中未受累者和100名正常对照者未检测到该突变.在该家系所有成员中未检测到KRT10和KRT9基因突变.结论:KRT1基因的错义突变(p.I479T)可能是导致该家系患者临床表型的病因.     

弥漫性掌跖角化病一家系角蛋白9基因检测

目的：检测弥漫性掌跖角化病一家系中的KRT9基因突变情况。方法：提取该家系中3例患者和3名家系正常成员及100名健康对照的外周血DNA,采取PCR扩增KRT9基因序列,ABI PRISM-3700测序仪检测KRT9基因突变情况。结果：该家系中3例患者存在KRT9基因上第487位C>T突变,而该家系的正常成员及健康对照未检测到突变。结论：KRT9基因基因突变C487T可能与本家系弥漫性掌跖角化病发病有关。     

表皮松解性掌跖角化病二家系基因突变检测

目的：检测表皮松解性掌跖角化病二家系患者致病基因。方法：收集二家系资料,提取二家系成员及100名（无亲缘关系）正常对照血样DNA,采取聚合酶链反应技术对KRT1、KRT9和KRT16基因进行扩增,并对其产物进行测序。结果：家系1先证者中检测到 KRT1基因突变c.598T>C（p.F200L）。家系2三例患者中检测到KRT9基因含杂合突变c.488G>A（p.R163Q）。而家系正常成员及家系外无亲缘关系的100名正常对照中均不存在以上突变。结论：本研究表皮松解性掌跖角化病二家系发病与KRT1、KRT9基因突变有关,且KRT1基因突变p.F200L为国内首次报道。     

表皮松解性掌跖角化症家系KRT9基因突变与临床表型分析

目的明确1个表皮松解性掌跖角化症(EPPK)家系的致病基因突变,为开展遗传咨询及产前诊断提供依据。方法收集家系内所有患者的临床表型资料,并采集血样提取基因组DNA,采用包含表皮松解性掌跖角化症相关基因的二代测序Panel结合Sanger测序验证的方法检测该家系的基因突变。结果该家系所有患者均在KRT9基因检测到c.1373TC(p.Leu458Pro)的杂合突变,该突变位于角蛋白9(K9)高度保守的螺旋2B区,该家系患者均未出现已有报道中检测到该突变患者存在的指节垫和先天性指屈曲症状。结论 KRT9基因c.1373TC(Leu458Pro)的杂合突变为本研究中EPPK的遗传学病因,同一突变在不同家系或不同个体之间的临床表型存在差异。     

表皮松解性角化过度型鱼鳞病两家系基因突变研究

目的 探讨两个表皮松解性角化过度型鱼鳞病（EHK）家系的基因突变情况。 方法 收集两个EHK家系的临床资料,提取外周血DNA,通过PCR扩增角蛋白基因KRT1和KRT10编码区的全部外显子及其侧翼序列并测序,以表型正常家系成员及50例健康人作为对照。结果 发现两个家系中患者均存在KRT10基因突变,分别为KRT10的剪接位点突变c.1030-2A > G和错义突变c.467G > A,在家系中健康人及健康对照者未发现上述突变。结论 剪接位点突变c.1030-2A > G和错义突变c.467G > A,可能分别是导致这两个家系临床表型的原因。     

伴指间关节畸形的掌跖角化病家系基因突变检测

目的：检测一掌跖角化病家系致病基因的突变。方法：收集一具有4例患者的掌跖角化病家系和50位正常人的血液样本，抽提基因组DNA，PCR扩增致病基因（角蛋白9基因，KRT9）的外显子区，测序分析PCR产物。结果：该家系中4例患者的KRT9基因第1外显子第160位密码子发生AAT→AGT的突变，导致第160位的天门冬氨酸被丝氨酸取代（N160S），正常人中未发现此突变。结论：KRT9基因的AAT→AGT突变（N160S）是导致该家系发生弥漫性掌跖角化病的原因。     

一个表皮松解性掌跖角化病家系的KRT1基因突变分析

目的 探讨一个中国汉族人表皮松解性掌跖角化病(EPPK)家系的角蛋白基因KRT1、KRT9、KRT10突变情况.方法 收集1个EPPK家系的临床资料,提取外周血DNA,通过PCR扩增角蛋白KRT1、KRT9、KRT10基因编码区的全部外显子及其侧翼序列并测序,以表型正常家系成员及50例健康人为正常对照.结果 发现家系内6例患者均存在KRT1基因错义突变c.1436T>C,导致第479位的异亮氨酸被苏氨酸取代(I479T),在家系中6例正常人及50例对照者未发现上述突变.结论 错义突变KRTI的c.1436T>C可能为导致该家系临床表型的主要原因.本例为国内首次发现的KRT1突变引起的EPPK家系.

Abstract：

Objective To analyze the mutations in keratin 1 (KRT1), KRT9 and KRT10 genes in a Chinese family with epidermolytic palmoplantar keratoderma (EPPK). Methods Clinical data were collected from a family with EPPK. Genomic DNA was extracted from the peripheral blood of 12 family members, including 6 patients and 6 unaffected members, as well as from 50 unrelated normal human controls. PCR was performed to amplify all the exons and flanking sequences of KRT1, KRT9 and KRT10 genes followed by DNA sequencing.Results A missense mutation C.1436T > C was found in the highly conserved helix termination motif of KRT1 gene of all the patients, resulting in a substitution of isoleucine by threonine at position 479 of the KRT1 protein. No mutation was found in the unaffected members or unrelated controls. Conclusions The missense mutation C.1436T > C in K.RT1 gene is likely to be the main cause of the phenotype of EPPK in this family.This is the first report of a pedigree with KRT1 gene mutation-induced EPPK in China.     

Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene

BACKGROUND: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis strictly confined to the palms and soles, and usually associated with mutations in the keratin K9 gene (KRT9). Mutations in the keratin K1 gene (KRT1) have been shown to underlie a variety of phenotypes typically involving generalized epidermolytic hyperkeratosis, but in some cases the phenotype can be more regionally restricted. OBJECTIVES: To identify the genetic defect in two unrelated families initially presenting with EPPK but where careful examination revealed hyperkeratosis extending on to the proximal wrist flexure. Methods Linkage analysis and DNA sequencing. RESULTS: We found that this phenotype is caused by a heterozygous missense mutation in the K1 gene, designated I479T. This mutation lies in the highly conserved helix termination motif of K1, previously shown to be important for keratin assembly and filament formation. In general, mutations in this region of keratins are associated with more severe disease phenotypes. However, K1 mutations in this region and the I479T mutation in particular have previously been associated with both severe and mild bullous congenital ichthyosiform erythroderma phenotypes. When further clinical enquiries were made, several affected individuals in the families studied here were found to have had transient flexural peeling and hyperkeratosis in the neonatal period. CONCLUSIONS: K1 mutations may underlie a phenotype closely resembling EPPK. A history of transient flexural peeling and hyperkeratosis in childhood and palmoplantar keratoderma which extends beyond the boundary of the palmoplantar margins may indicate a K1 mutation rather than a K9 defect. As K1 mutations are also associated with severe widespread phenotypes, with important implications for prognostic and genetic counselling, whole body examination is recommended for patients presenting with EPPK.     

Keratin-9 gene mutation in a family with epidermolytic palmoplantar keratoderma

BACKGROUND: Epidermolytic palmoplantar keratoderma is an autosomal dominant inherited disorder of keratinization. METHODS: We studied five members of a Jewish family with epidermolytic palmoplantar keratoderma. Genomic DNA was extracted from leucocytes, and exon 1 of the keratin 9 gene was amplified using polymerase chain reaction techniques. RESULTS: The mutation was found in exon 1 of the keratin 9 gene in codon 160. CONCLUSIONS: Like most of the other families with clinical features of epidermolytic palmoplantar keratoderma the mutation is found in exon 1 of the keratin 9 gene.     

A novel mutation in the L12 domain of keratin 1 is associated with mild epidermolytic ichthyosis

Summary Background Epidermolytic ichthyosis (EI), previously termed bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a clinically heterogeneous genodermatosis caused by mutations in the genes encoding the suprabasal keratins 1 and 10. Classical EI is clinically characterized by severe neonatal erythroderma, blistering and fragile skin in infancy, quickly subsiding with subsequent development of generalized scaling hyperkeratosis. We report three Dutch families with palmoplantar keratoderma and mild blistering, but without neonatal erythroderma and generalized scaling. A novel heterozygous missense mutation in the linker L12 domain of KRT1:c.1019A>G, p.Asp340Gly was found associated with this phenotype in these families. Objectives To investigate the effects of the novel KRT1:p.Asp340Gly and the one other previously reported KRT1:p.Asp340Val mutations on keratinocyte cytoskeleton formation and stress resistance. Methods Wild‐type and mutant pEGFP‐KRT1 fusion constructs were transfected into HaCaT cells and exposed to hypo‐osmotic shock. Haplotyping and genealogical studies were performed to investigate the possibility of a common founder for p.Asp340Gly. Results Cells transfected with either one of the keratin 1 L12 domain mutations showed significantly increased tonofilament aggregation. The haplotype around the KRT1 gene was shared in all affected family members of two families and a common founder was traced. Conclusions Our study supports the pathogenicity of the keratin 1 L12 domain mutations in vitro. These mutations are associated with a milder EI phenotype with pronounced palmoplantar keratoderma, and without neonatal erythroderma and scaling. The KRT1:p.Asp340Gly mutation in the Dutch families is likely to have arisen from a common founder.