Keratin 17 mutation in pachyonychia congenita type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity

Pachyonychia congenita type 2 (PC-2) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, focal keratoderma, multiple pilosebaceous cysts, and other features of ectodermal dysplasia. It has been demonstrated that PC-2 is caused by mutations in the keratin 17 and keratin 6b genes. In this report, we describe a missense mutation in the keratin 17 gene, M88T, in a Korean patient whose phenotype included early onset steatocystoma multiplex and Hutchinson-like tooth deformities along with other typical features of PC-2 such as hypertrophic nails, natal teeth and follicular hyperkeratosis.     

多发性脂囊瘤一家系KRT17基因的突变研究

目的: 研究一中国汉族人多发性脂囊瘤(SM)家系KRT17基因的突变情况,了解SM和KRT17基因异常的关系.方法: 采用聚合酶链反应(PCR)扩增该家系成员的KRT17基因第1号外显子,并对PCR产物进行序列分析.结果: 该家系中有5例患者KRT17基因的1号外显子第281位碱基鸟嘌呤(G)被腺嘌呤(A)所替代,导致第94位的精氨酸被组氨酸取代(R94H),而该家系中有2名正常人及与该家系无关的100名正常人中未发现此突变.结论: 首次报道在中国汉族人SM家系中发现KRT17基因的错义突变c.281G>A(p.R94H),该突变为本研究中所有患者的致病突变.     

多发性脂囊瘤家系角蛋白17基因突变的研究

目的:检测一多发性脂囊瘤(SM)患者家系基因突变。方法:应用聚合酶链反应(PCR)扩增患者外周血基因组DNA KRT17基因的所有8个外显子及邻近内含子区域,对其产物直接测序和序列分析基因突变。结果:该家系6位患者KRT17基因4号外显子区域及相邻内含子区域检测到3个多态性位点,在热点突变区域及其他外显子区域均未检测到致病基因突变。结论:角蛋白17基因编码区域的变异不是引起此SM家系的致病基因突变,提示SM可能具有遗传异质性。     

Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts

BACKGROUND: Pachyonychia congenita (PC) is a group of autosomal dominant ectodermal dysplasias caused by mutations in four differentiation-specific keratin genes. Two major clinical subtypes of PC have been generally recognized. Symmetrically thickened fingernails and toenails are the defining characteristic of PC type 2 (PC-2) with onset at infancy. Pilosebaceous cysts are the best hallmark of PC-2, but they usually occur at puberty. OBJECTIVES: To report a Chinese pedigree of PC-2 with unusually early onset sebaceous cysts and to explore the genetic mutation and its phenotype. METHODS: Exon 1 of keratin 17 was amplified by polymerase chain reaction (PCR) from genomic DNA from the three patients in the pedigree, the proband, his half-sister and his younger son, two unaffected members in the pedigree and 50 unrelated and unaffected people. PCR products were directly sequenced to detect the mutation. RESULTS: Direct sequencing of the PCR products revealed a heterozygous 275A-->G mutation in all three affected members. This mutation predicts the substitution of asparagine by serine in codon 92 (N92S) located in the 1A domain of keratin 17. CONCLUSIONS: Mutation in the 1A domain of keratin 17 underlies the affected members' phenotype, PC-2 with early onset sebaceous cysts and late-onset thickened fingernails and toenails. The onset of the cysts is very early in some people within this family and the age at onset of thickened fingernails and toenails is variable within the family, implying the existence of modifying factors.     

A mutation detection strategy for the human keratin 6A gene and novel missense mutations in two cases of pachyonychia congenita type 1

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by hypertrophic nail dystrophy, focal non-epidermolytic palmoplantar keratoderma and variable features of oral leukokeratosis and follicular keratosis. Previously, we have shown that this disease can be caused by mutations in type I keratin K16 and one mutation has been reported in its type II keratin expression partner, K6a. Mutation analysis for K6a has been hampered by the presence of multiple copies of the K6 gene in the human genome, of which some are expressed and others are pseudogenes. Here, we describe a mutation detection strategy where the entire KRT6A gene, approximately 7 kb, is specifically amplified by long-range PCR. Using this technique, we have detected two novel mutations in the 1A domain of the K6a polypeptide, N171K and F174S. Mutations were confirmed in the affected individuals and were excluded from 50 unaffected unrelated individuals by restriction enzyme analysis of KRT6A PCR products. Additionally, mutation N171K was confirmed by RT-PCR in mRNA derived from lesional palmoplantar epidermis of an affected individual, confirming the specificity of the genomic PCR for the functional K6a gene. This, together with a similar strategy which we have developed for the K16 gene, provide a robust system for mutation detection and prenatal diagnosis for patients with PC-1.     

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.     

A novel missense mutation L468Q of keratin 6a in pachyonychia congenita type 1

BACKGROUND: Pachyonychia congenita is an autosomal dominant disorder that usually develops in early infancy. The major features of the syndrome are hypertrophic nail dystrophy, palmoplantar keratoderma and oral leucokeratosis, accompanied by other ectodermal defects, according to subtype. OBJECTIVE: To analyse the K6a gene mutation in a sporadic Chinese patient with pachyonychia congenita type 1 (PC-1) and to explore the relationship between the genotype and phenotype of PC-1. METHODS: Genomic DNA was extracted from peripheral blood of the patient with PC-1 and 100 unrelated controls. The whole coding region of K6a gene was amplified using long-range polymerase chain reaction (PCR); nested PCR was then used to amplify the mutation 'hot-spot' of the K6a gene. The PCR products were directly sequenced to detect the mutation. RESULTS: A novel missense mutation L468Q in the helix 2B domain of the K6a polypeptide was identified in the patient but not in the healthy individuals from the family and 100 unrelated control individuals. CONCLUSIONS: We describe this mutation for the first time, and provide further evidence that the helix boundary motif sequences of K6a are a mutation 'hot-spot'.     

KRT6a基因N172del新发突变导致I型先天性厚甲症

目的：检测1例I型先天性厚甲症患者KRT6a基因突变。方法：提取该患者及其父母和100名正常对照外周血白细胞基因组DNA,设计针对KRT6a和KRT16基因的特异性引物,PCR扩增KRT6a和KRT16基因的全部外显子,并进行直接测序。结果：PCR扩增结合DNA测序发现该患者KRT6a基因第1外显子存在异常,第514—516位的3个核苷酸AAC缺失,导致第172位氨基酸一天冬酰胺（N）缺失。患者父母及100名正常对照均未发现此突变。未发现KRT16基因突变。结论：KRT6a基因N172del突变可能是导致本例I型先天性厚甲症的致病突变,该突变非遗传自父母,为新发突变。     

Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16

A young girl with clinical features of pachyonychia congenita type 1 was unusual in that the typical skin and nail changes were not noted until the age of 6 years. Direct sequencing of the KRT16A gene, encoding keratin K16, revealed a novel mutation K354N in the central 2B domain of the K16 polypeptide. The mutation created a new BsmI restriction site and therefore, the mutation was confirmed in the patient and excluded from both parents and 50 normal, unrelated individuals by BsmI digestion of KRT16A polymerase chain reaction products. This is the first time a mutation has been described in this location in a keratin other than K14, where similar mutations cause the milder Weber–Cockayne and/or Köbner types of epidermolysis bullosa simplex.     

Missense mutation in exon 7 of TRPS1 gene in an Italian family with a mild form of trichorhinophalangeal syndrome type I

BACKGROUND: Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant disorder, three types of which have been described in the literature. All of them are characterized by alopecia, facial dysmorphism and bone deformities. Deletions and nonsense mutations of the TRPS1 gene are responsible for most of the TRPS I and III cases with no clear genotype-phenotype correlation. The majority of missense mutations have been described at TRPS1 exon 6, encoding a presumptive GATA DNA-binding domain, and are known to be associated with the most severe forms of the phenotypic spectrum of TRPS. Mutation mapping at exon 7 described to date includes nonsense mutations and a familial case with an insertion mutation. OBJECTIVES: To determine a possible correlation between a mutation at exon 7 and mild TRPS phenotype. METHODS: We describe three members of an Italian family with TRPS I. All three showed clinical features typical of TRPS I such as temporal alopecia and facial abnormalities, but no mental retardation. RESULTS: Mutation analysis showed a missense mutation (R952C) in exon 7 of the TRPS1 gene. CONCLUSIONS: R952C is the first missense mutation described outside the GATA zinc-finger domain of TRPS1. In contrast with missense mutations occurring within this region, this mutation prevents the transport of the TRPS1 protein into the nucleus, therefore determining TRPS I by haploinsufficiency. We hypothesize that a TRPS exon 7 mutation could result in a mild phenotype.     

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。