Heredity of port-wine stains: Investigation of families without a RASA1 mutation

Background: The prevalence of capillary malformations, also known as port-wine stains (PWS), is 0.3%. Familial segregation can occur. The capillary malformation–arteriovenous malformation (CM-AVM) phenotype is caused by mutations in the RASA1 gene. In PWS familial cases, the inheritance is considered to be autosomal dominant with variable penetrance. Objective: Investigation of the heredity of PWS among patients who attended the vascular anomaly section at the Department of Dermatology in Malmoe, Southern Sweden, between 1993 and 2004 and to study the involvement of the RASA1 gene in patients with a positive family history of PWS. Subjects and methods: A total of 254 patients were examined and given a questionnaire regarding family history of PWS. The first group of 175 patients (109 females and 66 males) reported a negative family history. The other group of 65 patients (46 females and 19 males) reported a positive family history (50% parents or brothers and sisters). Results: The heredity of PWS was 27% (65/240). Twenty-one patients with a positive family history and relatives had no CM-AVM phenotype for mutations in the RASA1 gene. Conclusion: PWS may have a stronger heredity component than it was reported earlier and inheritance should be considered when counseling a patient. RASA1 mutations do not explain the PWS in our patients.     

RASA1 mutation in a family with capillary malformation–arteriovenous malformation syndrome: A discussion of the differential diagnosis

We describe a family who presented with several scattered, vascular, cutaneous lesions and was found to have a novel mutation in RASA1, diagnostic of capillary malformation–arteriovenous malformation syndrome. Our patient was initially given a presumptive clinical diagnosis of hereditary hemorrhagic telangiectasia. Capillary malformation–arteriovenous malformation syndrome shares several features with hereditary hemorrhagic telangiectasia and hereditary benign telangiectasia, but it can be distinguished clinically according to its morphologic appearance and distribution of cutaneous vascular lesions, the presence of internal fast‐flow lesions, and genetic analysis.     

一例合并枕部动静脉畸形和脊柱侧弯的神经纤维瘤病NF1基因突变分析

【摘要】 患者女,15岁。因全身多发咖啡斑15年、脊柱侧弯1年余就诊。1年前因枕部动静脉畸形手术切除肿物。皮肤科检查：全身散在多个大小不等咖啡斑,最大约3 cm × 4 cm,腋窝、腹股沟雀斑。全外显子测序显示,患者NF1基因第26号外显子发生碱基T杂合缺失（c.3328delT）移码突变。患者父母及弟弟均未发现该突变。诊断：神经纤维瘤病Ⅰ型合并枕部动静脉畸形和脊柱侧弯。     

Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa

Abstract:  Dystrophic epidermolysis bullosa (DEB) is inherited in both an autosomal dominant DEB and autosomal recessive manner RDEB, both of which result from mutations in the type VII collagen gene ( COL7A1 ). To date, 324 pathogenic mutations have been detected within COL7A1 in different variants of DEB; many mutations are clustered in exon 73 (10.74%) which is close to the 39 amino acid interruption region. Dominant dystrophic epidermolysis bullosa usually involves glycine substitutions within the triple helix of COL7A1 although other missense mutations, deletions or splice-site mutations may underlie some cases. In recessive dystrophic epidermolysis bullosa, the mutations include nonsense, splice site, deletions or insertions, 'silent' glycine substitutions within the triple helix and non-glycine missense mutations within the triple helix or non-collagenous NC-2 domain. The nature of mutations in COL7A1 and their positions correlate reasonably logically with the severity of the resulting phenotypes.     

外胚叶发育不良-皮肤脆性综合征一家系基因突变研究

目的:对国内首例外胚叶发育不良-皮肤脆性综合征的家系进行基因突变的研究。方法:收集家系资料,提取外周血DNA,采用PCR扩增斑菲素蛋白1(plakophilin1,PKP1)基因的编码区全部外显子,DNA直接测序,明确突变位点。针对所发现的突变以SmaⅠ或BsrSⅠ酶进行限制性内切酶检测。应用逆转录(RT)-PCR进一步明确家系的致病原因。结果:先证者PKP1基因有3个突变。第5外显子供体端杂合剪接突变(INS5+1G>T),第5外显子杂合的同义突变(1053T>A),这两种突变位于同一条等位基因上,由母亲遗传而来。第10内含子剪接受体端杂合突变(INS10-2A>G),由父亲遗传而来。这3种突变为国际首次报道。突变可能导致无义突变介导的mRNA降解。结论:在1例外胚叶发育不良-皮肤脆性综合征的先证者中检出有PKP1基因的复合性杂合突变,它们分别由无症状的致病基因携带者父母遗传而来。     

Four novel mutations in ATP2C1 found in Chinese patients with Hailey-Hailey disease

BACKGROUND: Familial benign chronic pemphigus or Hailey-Hailey disease (HHD; OMIM 169600) is an autosomal dominant blistering disease. Pathogenic mutations in ATP2C1 encoding a novel Ca2+ pump have recently been identified. OBJECTIVES: To identify mutations in ATP2C1 in Chinese patients with HHD. METHODS: Eleven unrelated Chinese patients with HHD were subjected to mutation detection in ATP2C1. Eight of them had a family history of HHD. The 27 coding exons and their flanking sequences were amplified and sequenced. RESULTS: Five of the 11 patients were identified to have heterozygous mutations including three nonsense mutations and two splicing mutations in ATP2C1. CONCLUSIONS: Four novel mutations, nonsense mutations S887X and W795X and splicing mutations 118-1 g-->a and 1890+1del(gtgag)ins53, were found in this series of Chinese patients with HHD.     

遗传性血管性水肿C1INH基因1440V变异及其对结构的影响

目的 通过基因测序了解遗传性血管性水肿(HAE)患者C1酯酶抑制剂(C1INH)基因第八外显子的变异情况.方法 从HAE患者外周血白细胞中提取基因组DNA,PCR扩增第八外显子片段后插入pUC19质粒载体冉转化入感受态大肠杆菌TG1菌株,培养扩增质粒DNA,提取纯化后进行基因测序.将患者血清进行SDS-PAGE及Westem印迹,以了解该变异对CIINH结构的可能影响.结果 在1例I型HAE患者的第八外显子中发现一个变异位点,16776A＞G,致440位的异亮氨酸突变成缬氨酸(1440V),SDS-PAGE及Westem印迹显示该患者血清中C1INH全部表现为96 000片段而非正常的105 000片段.结论 1440v是一个新的C1INH基因变异,位于C1INH反应中心环的P4位,变异可能导致C1INH分子构象发生改变.     

Identification of two novel nonsense mutations in the transglutaminase 1 gene in a Hungarian patient with congenital ichthyosiform erythroderma

Congenital ichthyosiform erythroderma (CIE) belongs together with lamellar ichthyosis (LI) to the group of autosomal recessive congenital ichthyoses (ARCI). Mutations in the transglutaminase (TGase) 1 gene (TGM1) have been identified in several families with LI and in some families with CIE. We report a case of CIE with two new nonsense mutations: a C7780G transversion in exon 11 resulting in a premature stop codon at aminoacid residue Y503X and a C8533G transversion in exon 13 leading to a nonsense mutation at S669X. These mutations were also identified in a heterozygous pattern in the unaffected parents. These two termination-codons result in the translation of a truncated protein at the C-terminal end domain of the TGM 1 molecule. B.C1 monoclonal antibody failed to detect TGase 1 in the patient's skin sample, and TGase activity measured by monodansyl cadaverine-incorporation showed the reduced TGase activity at the distribution of TGase 1 in the epidermis.     

A novel mutation in exon 8 of C1 inhibitor (C1INH) gene leads to abolish its physiological stop codon in a large Chinese family with hereditary angioedema type I

C1 inhibitor (C1INH) plays an important role in the classical pathway of the complement system. Mutations in C1INH gene cause quantitative or qualitative deficiencies in C1INH, which can lead to hereditary angioedema (HAE) type I or II. Here, we identified a novel frame‐shift mutation c.1391‐1445del55 (p.v464fsx556) in exon 8 in a large Chinese family with HAE type I. This 55 base pairs deletion abolishes the original stop codon and introduces a new stop codon 220 bp downstream of the original one, and leads to mutated C1INH protein prolonged from 500 to 556 amino acids. The levels of C4 and C1INH as well as C1INH activity in serum were significantly reduced in affected individuals. This is the first report of a novel mutation abolishing the physiological stop codon of C1INH gene in a large Chinese family with HAE type I.     

Identical COL71A1 heterozygous mutations resulting in different dystrophic epidermolysis bullosa phenotypes

Dystrophic epidermolysis bullosa is a rare blistering condition caused by mutations in the COL7A1 gene. Different clinical variants have been described, with dominant and recessive inheritance, but no consistent findings have been elucidated to establish a genotype–phenotype correlation. We present three unrelated patients with two identical pathogenic compound heterozygous mutations in the COL7A1 gene that developed different clinical forms of dystrophic epidermolysis bullosa—epidermolysis bullosa pruriginosa and mild recessive non‐Hallopeau–Siemens—raising the possibility of other genetic or environmental modifying factors responsible for the phenotype of the disease.     

Six novel mutations of the ADAR1 gene in patients with dyschromatosis symmetrica hereditaria: histological observation and comparison of genotypes and clinical phenotypes

Dyschromatosis symmetrica hereditaria (DSH), is a pigmentary genodermatosis of autosomal dominant inheritance. Since we clarified that the disease is caused by a mutation of the adenosine deaminase acting on the RNA 1 gene (ADAR1) in 2003, the molecular pathogenesis of a peculiar clinical feature of the disease has been expected to be clarified. We examined five familial cases and one sporadic case of Japanese families with DSH. The mutation analyses were done with single-strand conformation polymorphism/heteroduplex (SSCP/HD) analysis and direct sequencing of ADAR1. The DNA analysis of each patient revealed one missense mutation (p.F1091S), two nonsense mutations (p.C893X, p.S581X) and three frame-shift mutations (p.E498fsX517, p.F1091fsX1092, p.L855fsX856). Visual and electron microscopic findings showed abundant melanin pigment deposited all over the basal layer, and enlarged melanocytes with long dendrites located in the pigmented lesions with small or immature melanosomes scattered sparsely in the cytoplasm, but in the adjacent keratinocytes many small melanosomes were singly dispersed or aggregated. The hypopigmented areas showed little melanin deposition and reduced numbers of melanocytes in which much degenerative cytoplasmic vacuole formation could be observed by electron microscopy. Herein, we report six cases of DSH with six novel mutations. The variety of their clinical phenotypes even in the pedigree may suggest the presence of factors other than the ADAR1 gene influencing the extent of the clinical skin lesion. Microscopic findings suggest that the clinical appearance must have developed directly by melanocyte variations mainly induced by the ADAR1 gene mutations.     

Four novel ATP2C1 mutations in Chinese patients with Hailey–Hailey disease

Hailey–Hailey disease (HHD) is a kind of autosomal dominant dermatosis. The ATP2C1 gene has been identified as the pathogenic gene of HHD since 2000. In this study, direct DNA sequencing was used to identify ATP2C1 gene mutations in four Chinese families and two sporadic cases with HHD. The entire coding and flanking intronic sequences of ATP2C1 were screened for mutations and five heterozygous mutations of the ATP2C1 gene were detected in the four pedigrees and two sporadic cases with HHD. Four of them were novel, including three frame‐shift mutations (c.1330delC, c.888_889insT, c.478_479insA) and one nonsense mutation (c.1720C>T). These data added new variants to the database of ATP2C1 mutations associated with HHD.     

Heterogeneous mutations of the ATP2C1 gene causing Hailey–Hailey disease in Hong Kong Chinese

Background Hailey–Hailey disease (HHD) is a rare autosomal dominant dermatosis. It causes suprabasilar acantholysis leading to vesicular and crusted erosions affecting the flexures. Mutation of ATP2C1 gene encoding the human secretory pathway Ca²⁺/Mn²⁺‐ATPase (hSPCA1) was identified to be the cause of this entity. Objective The aim of this study was to study the mutational profile of the ATP2C1 gene in Hong Kong Chinese patients with HHD. Methods Patients with the clinical diagnosis of HHD proven by skin biopsy were included in this study. Mutation analysis was performed in 17 Hong Kong Chinese patients with HHD. Results Ten mutations in the ATP2C1 gene were found. Six of these were novel mutations. The novel mutations included a donor splice site mutation (IVS22+1G>A); a missense mutation (c.1049A>T); two deletion mutations (c.185_188delAGTT and c.923_925delAAG); an acceptor splice site mutation (IVS21‐1G>C) and an insertion mutation (c.2454dupT). Conclusion The six novel mutations provide additions to the HHD mutation database. No hot‐spot mutation was found and high allelic heterogeneity was demonstrated in the Hong Kong Chinese patients.