Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis.
Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis.
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DOI：
10.1136/jmedgenet-2012-101325
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发表时间：
2013-04
影响因子：
4
通讯作者：
Young TL
中科院分区：
文献类型：
--
作者：
Soler VJ;Tran-Viet KN;Galiacy SD;Limviphuvadh V;Klemm TP;St Germain E;Fournié PR;Guillaud C;Maurer-Stroh S;Hawthorne F;Suarez C;Kantelip B;Afshari NA;Creveaux I;Luo X;Meng W;Calvas P;Cassagne M;Arné JL;Rozen SG;Malecaze F;Young TL
角膜上皮内角化不良是一种极为罕见的疾病。影响美洲原住民Haliwa-Saponi部落成员的经典形式被称为遗传性良性上皮内角化不良（HBID）。在此，我们提出了一种新形式的角膜上皮内角化不良，我们通过使用深度测序技术确定了致病基因。一个七人的法国白人家庭与两个角膜上皮内角化不良影响的个人（6岁的先证者和他的母亲）被确定。先证者表现为双侧完全性角膜混浊和角化不良。掌跖角化过度和喉角化不良与表型相关。角膜和声带活检的组织学研究显示角化不良性角化。定量PCR排除了HBID病例中典型描述的4 q35重复。使用Illumina Hi Seq和全外显子组捕获处理进行下一代测序，平均覆盖率为50×。比对序列读数，并筛选单核苷酸变体和插入/缺失调用。进行了内部管道过滤分析，并与可用数据库进行了比较。发现NLRP 1基因的一个新的错义突变M77 T，其定位于染色体17p13.2。这是先证者母亲的一个新生突变，在家庭中分离后，在738个对照DNA样本中没有发现。在成人角膜上皮中测定NLRP 1表达。发现氨基酸的变化显着破坏蛋白质结构的稳定性。我们描述了一种新的角膜上皮内角化不良和我们如何确定其致病基因。NLRP 1基因产物与炎症、自身免疫性疾病和半胱天冬酶介导的细胞凋亡有关。NLRP 1基因多态性与多种疾病相关。
Corneal intraepithelial dyskeratosis is an extremely rare condition. The classical form, affecting Native American Haliwa-Saponi tribe members, is called hereditary benign intraepithelial dyskeratosis (HBID). Herein, we present a new form of corneal intraepithelial dyskeratosis for which we identified the causative gene by using deep sequencing technology. A seven member Caucasian French family with two corneal intraepithelial dyskeratosis affected individuals (6-year-old proband and his mother) was ascertained. The proband presented with bilateral complete corneal opacification and dyskeratosis. Palmoplantar hyperkeratosis and laryngeal dyskeratosis were associated with the phenotype. Histopathology studies of cornea and vocal cord biopsies showed dyskeratotic keratinisation. Quantitative PCR ruled out 4q35 duplication, classically described in HBID cases. Next generation sequencing with mean coverage of 50× using the Illumina Hi Seq and whole exome capture processing was performed. Sequence reads were aligned, and screened for single nucleotide variants and insertion/deletion calls. In-house pipeline filtering analyses and comparisons with available databases were performed. A novel missense mutation M77T was discovered for the gene NLRP1 which maps to chromosome 17p13.2. This was a de novo mutation in the proband’s mother, following segregation in the family, and not found in 738 control DNA samples. NLRP1 expression was determined in adult corneal epithelium. The amino acid change was found to destabilise significantly the protein structure. We describe a new corneal intraepithelial dyskeratosis and how we identified its causative gene. The NLRP1 gene product is implicated in inflammation, autoimmune disorders, and caspase mediated apoptosis. NLRP1 polymorphisms are associated with various diseases.
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DOI：
10.1093/bioinformatics/btq224
发表时间：
2010-08-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Katoh K;Toh H
通讯作者：
Toh H
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
--
作者：
Dithmar, S;Stulting, RD;Grossniklaus, HE
通讯作者：
Grossniklaus, HE
影响因子：
9.8
作者：
Allingham, RR;Seo, B;Vance, JM
通讯作者：
Vance, JM
影响因子：
4.6
作者：
AuBuchon, J. P.;de Wildt-Eggen, J.;Dumont, L. J.
通讯作者：
Dumont, L. J.