板层状鱼鳞病一家系TGM1突变基因检测

目的 报道1例有近亲背景的板层状鱼鳞病患者及其家系,并检测其转谷氨酰胺酶Ⅰ编码基因TGM1的突变。 方法 提取板层状鱼鳞病患者及家族成员的基因组DNA,采用PCR 扩增TGM1 基因所有的15个外显子及其邻近的侧翼序列并进行双向直接测序。结果 该板层状鱼鳞病患者TGM1基因第11个外显子的1666位的碱基存在胞嘧啶（C）→胸腺嘧啶（T）突变,使得529位密码子由ACA→ATA,相应氨基酸由苏氨酸（Thr）变为异亮氨酸（Ile）。结论 患者转谷氨酰胺酶Ⅰ Thr529Ile基因突变可能导致其发病。其父母基因型均为该突变的杂合子,近亲婚配促进基因的纯合,增加后代患病概率。     

板层状鱼鳞病TGM1基因突变研究

目的 探讨一个板层状鱼鳞病家系转谷氨酰胺酶1基因(TGM1)的突变.方法 提取板层状鱼鳞病患者及家族成员的基因组DNA,采用PCR扩增TGM1基因所有的外显子及其邻近的剪切点并进行双向直接测序,并对TGM1基因的同源性进行分析.结果 板层状鱼鳞病患者TGM1基因存在异常:外显子3的第504位碱基由胞嘧啶突变为胸腺嘧啶,使第142位氨基酸由精氨酸(R)转变为半胱氨酸(C),即R142C错义突变;外显子7的第1122位碱基由胞嘧啶突变为胸腺嘧啶,使348位氨基酸由精氨酸(R)突变为终止密码(R348X),导致其编码的蛋白缺失了C端的470个氨基酸.其父亲为R142C杂合子,母亲为R348X突变杂合子;R142C错义突变位于TGM1基因保守区域.结论 该板层状鱼鳞病患者存在转谷氨酰胺酶1基因的R142C错义突变和R348X无义突变.     

板层状鱼鳞病致病基因的研究进展

板层状鱼鳞病(lamellar ichthyosis,LI)是一组以皮肤干燥、鱼鳞状鳞屑为特征的角化异常性皮肤病。随着分子生物学的发展,对LI致病基因的研究不断深入,现已明确致病基因TGM1、AB￣CA12、CYP450、ALOXE3和ALOXl2B,他们分别通过不同的途径如影响角质形成细胞包膜的形成、脂质转运体、脂质代谢等来改变皮肤的屏障功能导致LI的发生。此外,一些报道其他基因(NIPAL4基因)也可导致LI的发生,但具体机制不详。本文主要对5个明确致病基因进行综述,更好地了解致病基因功能及导致LI发生的具体机制,为寻找新的药物治疗靶点提供必要的依据。     

板层状鱼鳞病二例

2例具有板层状鱼鳞病的典型皮损,全身皮肤灰褐色或灰棕色鳞屑,呈菱形、多角形或成大片,中央黏着,边缘游离高起,部分厚如铠甲.2例均有不同程度的眼睑、唇外翻及掌跖中度角化过度.例2皮损组织病理检查:角化过度,棘层及颗粒层增厚,表皮突延长,真皮浅层血管周围少量炎性细胞浸润.2例均口服阿维A胶囊,经尿素乳膏及鱼肝油软膏外用后,症状较前缓解.     

板层状鱼鳞病1例

板层状鱼鳞病（lamellar iehthyosis）是一咱常染色体隐性遗传性皮肤病，临床表现为全身大片状鳞屑，同时伴有掌跖角化过度、出汗不良和眼睑外翻等特征。我科收治1例，现报告如下。     

板层状鱼鳞病与谷氨酰胺转移酶

板层状鱼鳞病(Lamellar ichthyosis，LI)是一种常染色体隐性遗传性皮肤病，临床上以广泛的鳞屑和角化过度为其特征性表现。近来研究表明，部分LI患者的谷氨酰胺转移酶1(transglutaminase 1，TGasel)的编码基因—TGM1突变是其发病原因。     

板层状鱼鳞病1例

1　临床资料　患儿男 ,3岁。因全身皮肤反复红斑、脱屑 2年就诊。其母诉患儿出生后 ,全身皮肤干燥 ,但无红斑鳞屑。半岁时全身皮肤出现红斑 ,有少量细薄干燥鳞屑 ,无丘疹水疱 ,无糜烂渗液 ,继而红斑逐渐融合成片 ,鳞屑变大呈多角形或四方形 ,反复发作至今。 1岁半时 ,患儿出现双下眼睑外翻 ,十指指甲增厚。患儿系足月顺产 ,母孕期无上感及特殊用药史。父母非近亲婚配 ,家族中无类似皮肤病史。体检 :发育较差 ,体重 12kg。皮肤科情况 :头发较黄 ,头皮上覆细薄干燥鳞屑 ,全身皮肤除生殖器外弥漫性潮红、干燥 ,上覆大片多角形或方形淡黄色疏松…     

板层状鱼鳞病患者转谷氨酰胺酶1活性缺失及其基因突变

目的 检测一板层状鱼鳞病家系中患者转谷氨酰胺酶1的活性及其编码基因的突变。方法 以免疫组化法检测患者转谷氨酰胺酶1的活性,PCR扩增该基因的全部编码序列,并行DNA测序。结果 患者皮肤转谷氨酰胺酶1的活性完全缺失。PCR结合DNA测序发现患者该基因第4外显子存在异常:第604位碱基由胞嘧啶突变为胸腺嘧啶,使第202位氨基酸由谷氨酰胺(Q)变为终止密码(R202X),导致其编码的蛋白缺失了C端的615个氨基酸。其父母皆为杂合子。结论 板层状鱼鳞病患者转谷氨酰胺酶1的活性完全缺失,是其转谷氨酰胺酶1基因的无义突变,引起编码的蛋白缺陷。     

板层状鱼鳞病患者感染水痘1例

患者,男,27岁。因发热3天,全身水疱2天入院。2周前在我院因板层状鱼鳞病给予凡士林封包及口服阿维A后明显好转出院。本次入院查体:T 38.6℃,全身以头面、躯干和四肢近端为主的密集分布绿豆大小脓疱,少量水疱、斑丘疹,部分结痂,口腔内数个散在分布的粟粒样大小水疱。皮损组织病理示表皮内水疱,疱内可见多核上皮细胞,多量中性粒细胞。单纯疱疹病毒(HSV)病毒培养和DNA检测阴性。诊断:板层状鱼鳞病感染水痘。给予阿昔洛韦500 mg每8 h 1次,联合静脉用人丙种球蛋白10 g每日1次,连续3天,3天后体温降至正常,部分皮损干涸结痂,1周后患者痊愈出院。     

重症板层状鱼鳞病一例

患者,女,41岁。全身黑褐色片状鳞屑40余年,伴瘙痒3天。结合临床及组织病理检查,诊断符合板层状鱼鳞病。口服阿维A、药物封包治疗4周后病情好转。     

Lamellar ichthyosis with pseudoexon activation in the transglutaminase 1 gene

We report a case of a 12‐year‐old boy who was born as a collodion baby after which thick scales developed on his entire body surface. His younger brother showed a similar skin condition. Arcuate‐shaped, large, brownish scales covered his face with ectropion. His lower legs were also covered with larger thick, brownish, plate‐like scales, but other areas were covered with smaller scales. Next‐generation sequencing for exons and splice sites detected a stop‐gain TGM1 mutation leading to p.R71* in transglutaminase 1 (TG1). Another mutation identified was a cryptic mutation in intron 3 that activated a pseudoexon, which was detected by RNA‐based analysis of hair bulbs. The deep intronic mutation caused another truncation mutation, p.N171Tfs^*45, in TG1. An in situ TG1 assay demonstrated that TG1 activity was totally lost in this case. Thus, we conclude that the severe phenotype of the patient developed due to those novel compound heterozygous null truncation mutations in TGM1.     

Identification of mutations in the transglutaminase 1 gene in lamellar ichthyosis

Lamellar ichthyosis (LI) is an autosomal recessive disorder of cornification. Mutations in the transglutaminase 1 gene (TGM1) have been identified in several families with this disorder. We analyzed two unrelated families with offspring affected with LI. Family 1 included affected monozygotic twins, in which a homozygous G-to-T transversion was identified in exon 6 at amino acid residue R315L. This mutation was also identified in the unaffected mother. In family 2, which consisted of one affected infant, a T-to-G transversion in exon 8 resulted in a change of phenylalanine to valine, F400V, and a C-to-T transition in exon 4 resulted in a change of proline to leucine, P248L. In this family, the mutation F400V was found in the unaffected father, and the mutation P248L was identified in the unaffected mother. These findings extend the growing body of literature documenting mutations in the TGM1 gene as the molecular basis of certain cases of lamellar ichthyosis.     

Bathing suit ichthyosis: Two Burmese siblings and a review of the literature

Bathing suit ichthyosis (BSI) is a subtype of autosomal recessive congenital ichthyosis (ARCI) characterized by the development of large platelike scales mainly limited to the trunk. It is caused by temperature sensitive variants in transglutaminase 1, encoded by the gene TGM1. We describe a rare case of intrafamilial variation in phenotypic expressivity in two Burmese siblings with BSI that demonstrates the heterogeneity of the disorder within the same family and even in the same individual across time. We also present a concise review of the genotypic spectrum of BSI from 54 cases reported in the literature as evidence that both environmental and additional genetic factors can significantly alter the clinical phenotype.     

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.     

Prenatal ultrasound detection of collodion membrane in association with an autosomal recessive congenital ichthyosis due to transglutaminase 1 deficiency

We describe a case of collodion baby diagnosed prenatally by ultrasound. Classic signs (ectropion, flattened nose, and eclabion) were detected on routine ultrasound at 21 weeks of gestation. At birth, the presence of collodion membrane was confirmed and subsequently, the diagnosis of an autosomal recessive congenital ichthyosis due to compound heterozygosity of the TGM1 gene was made.     

Diagnosis of autosomal recessive lamellar ichthyosis with mutations in the TGM1 gene

BACKGROUND: Autosomal recessive lamellar ichthyosis (ARLI) is a clinically and genetically heterogeneous disorder. In many cases, mutations in the transglutaminase 1 gene (TGM1) have been identified, however, other clinically indistinguishable cases have been linked to chromosomes 2, 3 and 19. Previous studies have failed to establish any correlation between clinical characteristics and genetic mutations. OBJECTIVES: To investigate the molecular basis of ARLI in 10 patients with the typical clinical presentation of the disorder. METHODS: We performed polymerase chain reaction and direct sequencing-based mutation screening in all of these patients, and TGM1 immunofluorescence microscopy and in vitro enzyme activity assays in selected patients. RESULTS: Mutation screening revealed 14 mutations, four of which have been previously described. While immunofluorescence microscopy was negative in patients with non-sense mutations or out-of-frame insertions or deletions, the results were variable in cases with mis-sense mutations and in cases with no mutations in the TGM1 gene. In vitro enzyme activity assays gave results consistent with the mutation data. CONCLUSIONS: Our findings support the importance of mutation screening in the evaluation of ARLI.     

Basis for the permeability barrier abnormality in lamellar ichthyosis

The basis for the permeability barrier abnormality in lamellar ichthyosis (LI) is not known. LI is caused by mutations in the gene that encodes the enzyme, transglutaminase 1 (TGI), which is responsible for assembly of the cornified envelope (CE). TG1 also has been suggested recently to catalyze the covalent attachment of omega-hydroxyceramides (omega-OHCer) to the CE, forming the corneocyte-lipid envelope (CLE). We first assessed the barrier function and the permeability pathway of the water-soluble tracer, colloidal lanthanum, across the stratum corneum (SC) in patients with LI with absent (n = 4) or low (n = 2) TG1 activity/protein. Increased movement of tracer through the SC correlated with increased transcutaneous water loss, and tracer remained restricted to the SC interstices. Enhanced extracellular permeability, in turn, was explicable by truncation and fragmentation of extracellular lamellar membrane arrays. The resultant clefts in the SC interstices represent the likely pathway for increased water permeability. Moreover, tracer movement remained restricted to the interstices, despite the demonstration of increased corneocyte fragility associated with widespread variations in CE structure. Regardless of variability in CE structure, however, CLE structure and bound omega-OHCer content were normal. The normal CLE in LI may explain both the restriction of tracer to the SC interstices, as well as the presence of foreshortened membrane arrays with near-normal interlamellar dimensions. Finally, the demonstration of a normal CLE in LI also raises questions about the putative role of TG1 in forming the CLE. These results demonstrate: (1) the extracellular nature of increased permeability in LI; (2) discontinuities in extracellular membrane structures that account for the enhanced permeability in LI; (3) that these membrane abnormalities are both associated with and explained by abnormalities in the subjacent CE scaffold; and (4) an intact CLE is present in LI, despite abnormalities in the CE, which may restrict water movement to the SC interstices in LI.