先天性角化不良的一个新的基因突变

目的 检测一例先天性角化不良(DKC)患者DKC1基因的突变情况。方法 采用PCR技术扩增DKC1基因的15个外显子,然后采用变性高效液相色谱(DHPLC)技术进行基因突变筛查,对筛查结果异常的外显子进行DNA测序:基因突变的验证在100例无相关遗传性疾病的无关男性中进行。结果 患者DKC1基因的第12号外显子呈异常的DHPLC洗脱峰,家庭其他成员及正常群体对照未见此异常洗脱峰。测序结果显示患者DKC1基因第12外显子的1236位碱基由G→T,导致W412C突变,家庭其他成员及正常群体对照均未见此突变。结论 我们检测到的患者DKC1基因W412C是一个新的散发性突变,它可能导致患者先天性角化不良。     

一个先天性角化不良家系中DKC1基因突变的检测

目的 研究先天性角化不良(DKC)一家系的基因突变情况和遗传方式.方法 采用聚合酶链反应-DNA直接测序方法检测DKC1基因的突变,并用限制性内切酶酶切方法鉴定和检测DKC1基因的突变.结果 家系中2例患者均存在DKC1基因的1058C→T突变,从而导致编码蛋白—角化不良素(dyskerin)发生A353V突变.其母亲和姐姐为该突变的杂合子,但表型正常.结论 该家系为X性联隐性遗传型DKC,存在DKC1基因1058C→T突变.     

Dyskeratosis congenita in a 40-year-old patient

A 40-year-old patient with a 3-year history of thrombocytopenia was admitted with reticulated and speckled hyper- and hypopigmentations especially on the upper trunk. Aplasia or dystrophy of the fingernails and toenails as well as atresia of the lacrimal ducts were noted. Examination of the oropharynx revealed multiple mucosal leukoplakias and loss of almost all teeth. Based on these observations the diagnosis of X-linked dyskeratosis congenita (Zinsser-Cole-Engman syndrome, OMIM #305000) was made and confirmed by sequencing of the dyskerin 1 (DKC1) gene which revealed a missense mutation in exon 11.     

Epidermolytic palmoplantar keratoderma in a Hispanic kindred resulting from a mutation in the keratin 9 gene

Epidermolytic palmoplantar keratoderma (EPPK) is a localized keratinization disorder caused by mutations in the highly conserved coil 1A domain of the keratin 9 gene, KRT9. We present a Hispanic pedigree spanning three generations, with affected individuals in all generations. Using polymerase chain reaction amplification and direct sequencing we demonstrated a previously reported missense mutation in KRT9, which is expressed almost exclusively in the skin of palms and soles. The C-->T missense mutation R162W changes a basic amino acid (arginine) to a neutral amino acid (tryptophan). We describe this mutation in a Hispanic pedigree with EPPK for the first time, extending the finding of this mutation in other genetic backgrounds, and demonstrating the prevalence of this mutation in diverse populations.     

Dyskeratosis congenita bei einem 40-jährigen Patienten

A 40-year-old patient with a 3-year history of thrombocytopenia was admitted with reticulated and speckled hyper- and hypopigmentations especially on the upper trunk. Aplasia or dystrophy of the fingernails and toenails as well as atresia of the lacrimal ducts were noted. Examination of the oropharynx revealed multiple mucosal leukoplakias and loss of almost all teeth. Based on these observations the diagnosis of X-linked dyskeratosis congenita (Zinsser-Cole-Engman syndrome, OMIM #305000) was made and confirmed by sequencing of the dyskerin 1 (DKC1) gene which revealed a missense mutation in exon 11.     

Dyskeratosis congenita: a literature review

Dyskeratosis congenita is a rare hereditary disease that occurs predominantly in males and manifests clinically as the classic triad of reticulate hyperpigmentation, nail dystrophy and leukoplakia. It increases the risk of malignancy and other potentially lethal complications such as bone marrow failure, lung and liver diseases. Mutations in 19 genes are associated with dyskeratosis congenita, and a fifth of the pathogenic mutations are found in DKC1, the gene coding for dyskerin. This review aims to address the clinical and genetic aspects of the disease.     

Oral carcinoma in a young man: a case of dyskeratosis congenita

We report a 28-year-old male with a voluminous growth of the tongue, present for 6 months. The histological examination revealed a squamous cell carcinoma. The patient was also affected by oral leukoplakia, nail dystrophy, reticulated poikiloderma of the neck and hyperkeratosis of palms and soles. On the basis of clinical features and histological findings, as well as findings from the family, the diagnosis of dyskeratosis congenita (DKC) was made.     

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.     

常染色体隐性遗传先天性角化不良一例及TERT基因突变研究

【摘要】 目的 报告1例常染色体隐性遗传先天性角化不良,检测其致病基因突变情况。方法 采集先证者及其父母外周血,提取基因组DNA,以100例健康人作为对照,运用Illumina Nextseq500测序仪检测先证者家系皮肤病相关基因编码区域的序列突变情况,致病性突变经PCR?Sanger测序验证。运用生物信息学软件Clustalw2.0、PyMOL、PolyPhen?2、SIFT及FATHMM分别对基因突变位点的保守性、蛋白结构变化及致病性进行预测。结果 先证者临床表现为颈胸部网状皮肤异色、腋窝点状色素沉着,部分趾甲萎缩、表面粗糙及口腔黏膜白斑,血常规及肝功能指标部分异常。基因检测显示,先证者携带TERT基因c.2452G>A（p.Val818Met）与c.2594G>A（p.Arg865His）复合杂合突变,其中c.2452G>A突变在HGMD中未见收录。母亲携带c.2452G>A杂合突变,父亲及100例健康对照TERT基因未见突变。生物信息软件分析显示,多个物种TERT蛋白在818与865位氨基酸位点分别为高度保守与完全保守,基因突变后对应蛋白结构存在差异。依先证者临床表现、基因检测、辅助检查及生物信息分析结果,最终诊断为常染色体隐性遗传先天性角化不良。结论 TERT基因c.2594G>A（p.Arg865His）与c.2452G>A（p.Val818Met）复合杂合突变可能是导致该先证者临床表型的原因。     

A novel mutation in the second half of the keratin 17 1A domain in a large pedigree with delayed-onset 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. We report a large Chinese pedigree of typical delayed-onset PC-2 that includes 19 affected members. Direct sequencing of PCR products revealed a novel heterozygous 325A-->G mutation in the affected members. This mutation predicts the substitution of asparagine by aspartic acid in codon 109 (N109D) located in the second half of the keratin 17 1A domain, where similar mutation in keratin 5 is associated with the mild Weber-Cockayne form of epidermolysis bullosa simplex.     

Dyskeratosis congenita. Report of a large kindred

This kindred includes six males with dyskeratosis congenita. It is the largest British pedigree so far reported and brings the total number of reported cases to fifty-nine. Our pedigree supports X-linked recessive inheritance and close linkage with the Xg² locus was excluded. Three previously unreported complications are noted; Hodgkin's disease, adenocarcinoma of the pancreas and deafness. Normal chromosomal stability was found in three patients and immunological studies precluded an early universal defect in cell-mediated immunity.     

Epidermolysis Bullosa Simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP), characterized by trauma-induced blisters, distinct pigmentary changes of the trunk and extremities, and acral hyperkeratotic papules, is almost exclusively caused by a common KRT5 missense mutation affecting the V1 region of keratin 5. We studied the first Hispanic family, the largest single generation of affected family members in which 5 out of 10 siblings inherited EBS-MP from their affected father, as well a second large pedigree, the first reported of Finnish ancestry. In both families, the heterozygous transition mutation 74C-->T of the keratin 5 gene, which results in amino acid substitution P25L, completely co-segregated with the EBS-MP phenotype.     

Somatic ATP2A2 mutation in a case of papular acantholytic dyskeratosis: mosaic Darier disease

Papular acantholytic dyskeratosis, also known as acantholytic dermatosis of the vulvocrural (or anogenital) area, is an uncommon eruption reported predominantly in women. This entity manifests with pruritic papules in the groin/anogenital area and less commonly on the chest. The pathobiology of papular acantholytic dyskeratosis is uncertain. A 62‐year‐old woman presented with multiple verrucous‐appearing lesions in the groin and on the chest showing acantholytic dyskeratosis on histopathology. Given histological similarity of these papular acantholytic dyskeratosis lesions to Darier disease due to inherited ATP2A2 mutation, we screened affected and normal tissue and peripheral blood in our patient for mutations in ATP2A2. We found an identical ATP2A2 p.706D>N mutation in multiple independent papular acantholytic dyskeratosis lesions that was not present in uninvolved skin or peripheral blood DNA. These findings establish somatic mosaicism of ATP2A2 mutations as a genetic cause for papular acantholytic dyskeratosis.     

一对称性色素异常症家系ADAR基因突变分析及产前诊断

 目的:通过对一中国汉族对称性色素异常症(DSH)家系行ADAR基因突变检测,分析其致病性及诊断胎儿是否为DSH患者。方法：收集家系成员的临床资料和血样,应用高通量测序方法进行测序分析,应用聚合酶链反应(PCR)扩增结合Sanger测序对ADAR基因所有编码区进行测序,分别检测家系中2例患者(先证者及其父亲)、1例胎儿和8例正常人的突变情况。结果：该家系中2例患者及胎儿均携带ADAR基因c.613C>T(p.Q205X)位点杂合变异,另外8例未患病的家系成员均未发现上述突变。结论：ADAR 基因c.613C>T(p.Q205X)为引起该家系发生DSH的突变位点,而不是单核苷酸多态性(SNP)。该结果拓展了ADAR基因突变谱,为遗传性对称性色素异常症基因诊断和产前诊断提供参考和帮助。     

Mutations in the ATP2C1 gene in Chinese patients with Hailey-Hailey disease

Hailey-Hailey disease (HHD; MIM 16960) is a rare autosomal dominant hereditary disorder characterized by recurrent eruption of vesicles and bullae, predominantly involving the body folds. It is caused by heterozygous mutations in the ATP2C1 gene, encoding the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hSPCA1). When we studied Chinese patients with HHD, we found two different heterozygous mutations, Q506X and G353V, the former previously reported in a Hungarian patient, and the latter being a novel mutation. In a 38-year-old patient from a four-generation pedigree with a 3-year history of severe recurrent blisters, we identified a C-->T transition at nucleotide 1696, c(1696C-->T), in exon 17 of ATP2C1, resulting in a nonsenes mutation, Gln506X, which resulted in a premature termination codon. In the second patient, who represented a occurrence of sporadic Hailey-Hailey disease, a G-->T transversion of nucleotide, c(G1238T), in exon 13 of ATP2C1 was detected, which resulted in a Gly353-->Val amino acid substitution (G353V). Our molecular findings further demonstrate that the mutational events in the human ATP2C1 gene encoding the hSPCA1 pump play an important role in the pathogenesis of HHD.     

先天性角化不良1例及家系调查

报告1例先天性角化不良并附家系调查报告。先证者男,9岁。全身呈网状棕黑色色素沉着,LI腔黏膜白斑,牙齿排列不整齐,20甲营养不良。皮损组织病理检查示：表皮轻度角化,棘层明显变薄,基底层色素增加,真皮上部有较多噬黑素细胞。血染色体G带分析结果示：核型为46．XY,染色体正常。家族中另有3例男性患此病,其中2例已故。     

Weber-Cockayne亚型单纯型大疱性表皮松解症一家系报告

目的:研究Weber-Cockayne亚型单纯型大疱性表皮松解症(EBS-WC)一家系的基因突变,并进行产前诊断。方法:应用PCR及DNA直接测序方法明确突变位点,针对所发现的突变以限制性内切酶片段长度多态性(RFLP)分析加以验证,在此基础上于妊娠24周时对从胎儿羊水所提取的DNA进行测序及酶切验证。结果:该家系患者存在角蛋白(keratin,KRT)5基因突变:第7外显子第1388位碱基由胸腺嘌呤突变为胞嘧啶,导致第463位氨基酸由亮氨酸变为脯氨酸(L463P)。50名健康对照者不存在此突变。羊水细胞DNA不存在此突变的胎儿,出生后未患大疱性表皮松解症。结论:KRT5第7外显子的突变是引起该家系临床症状的特异性突变。     

A homozygous nonsense mutation in the EVER2 gene leads to epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is a genodermatosis with mainly autosomal recessive inheritance. Pathogenic mutations in two adjacent genes, EVER1 and EVER2, have recently been identified. In this study, we performed mutation detection for the EVER1 and EVER2 genes on samples from a Chinese patient with EV, who had consanguineous parents. A homozygous C-->T transition at nucleotide position 568 within exon 6 of the EVER2 gene was detected. The mutation led to a premature translation termination (R190X) and the predicted protein lacked 537 amino acids. This novel nonsense mutation is, to our knowledge, the first mutation reported in Chinese patients with EV.