Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.
Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.
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DOI：
10.1371/journal.pgen.1007168
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发表时间：
2018-01
期刊：
影响因子：
4.5
通讯作者：
Morasso MI
中科院分区：
文献类型：
--
作者：
Duverger O;Carlson JC;Karacz CM;Schwartz ME;Cross MA;Marazita ML;Shaffer JR;Morasso MI
先天性厚甲病（PC）是一种皮肤疾病，主要特征是指甲营养不良和疼痛性掌足角化病。PC是由KRT6A、KRT6B、KRT6C、KRT16和KRT17基因突变引起的，KRT6A、KRT6B、KRT6C、KRT16和KRT17是一组角蛋白基因，在甲床、掌跖表皮、口腔黏膜上皮、毛囊和汗腺中表达。RNA-seq分析显示，所有与pc相关的角蛋白（除了Krt6c确实存在于小鼠基因组中）都在小鼠牙釉质器官中表达。我们进一步证明，这些角蛋白是由成釉细胞产生的，并被纳入成熟的人牙釉质。利用来自573名成人和449名儿童的遗传和口腔内检查数据，我们发现了KRT6A、KRT6B和KRT6C的几种错义多态性，这些多态性会导致更高的龋齿风险。对一名携带角蛋白6a (K6a) p.Asn171Lys替换的PC患者的牙齿结构分析显示，牙釉质棒鞘破坏导致棒的形状和分布改变。最后，在两个KRT6基因中发现的这种与pc相关的替代以及更频繁的与龋齿相关的snp，导致p.Ser143Asn替代（KRT6B中的rs28538343和KRT6C中的rs151117600），改变了成釉细胞样细胞中K6丝的组装。这些结果发现了一组新的参与牙釉质形成的角蛋白，区分了蛀牙的新易感性位点，并揭示了先天性肿甲的其他临床特征。蛀牙，俗称蛀牙，是全世界儿童和成人中最常见的慢性疾病。它由产酸细菌破坏牙齿的外层牙釉质组成。牙釉质是人体最坚硬的组织，由96%的矿物质组成。然而，它含有一小部分蛋白质，这对它抵抗机械应力和腐烂很重要。在这里，我们发现这个蛋白质片段包含一组属于角蛋白家族的结构蛋白（K6a, K6b, K6c， K16和K17），它们特别存在于手掌和脚底的皮肤以及指甲中。我们进一步表明，影响这些蛋白质组成的常见基因突变导致蛀牙数量增加。这些角蛋白的罕见突变导致一种称为先天性厚甲癣（PC）的人类疾病，其特征是严重的指甲畸形和手掌和脚底皮肤病变。其中一名患者的智齿分析显示其牙釉质有结构性缺陷。这些结果表明，这些角蛋白是牙釉质的重要组成部分，编码它们的基因中的常见遗传变异会影响普通人群的蛀牙风险。
Pachyonychia congenita (PC) is a cutaneous disorder primarily characterized by nail dystrophy and painful palmoplantar keratoderma. PC is caused by mutations in KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. RNA-seq analysis revealed that all PC-associated keratins (except for Krt6c that does exist in the mouse genome) are expressed in the mouse enamel organ. We further demonstrated that these keratins are produced by ameloblasts and are incorporated into mature human enamel. Using genetic and intraoral examination data from 573 adults and 449 children, we identified several missense polymorphisms in KRT6A, KRT6B and KRT6C that lead to a higher risk for dental caries. Structural analysis of teeth from a PC patient carrying a p.Asn171Lys substitution in keratin-6a (K6a) revealed disruption of enamel rod sheaths resulting in altered rod shape and distribution. Finally, this PC-associated substitution as well as more frequent caries-associated SNPs, found in two of the KRT6 genes, that result in p.Ser143Asn substitution (rs28538343 in KRT6B and rs151117600 in KRT6C), alter the assembly of K6 filaments in ameloblast-like cells. These results identify a new set of keratins involved in tooth enamel formation, distinguish novel susceptibility loci for tooth decay and reveal additional clinical features of pachyonychia congenita. Tooth decay, more commonly known as dental cavities, is the most common chronic disease worldwide, both in children and in adults. It consists in the destruction of tooth enamel, the outer layer of the teeth, by acid-producing bacteria. Enamel is the hardest tissue in the body, comprised of 96% minerals. However, it contains a small fraction of proteins that is important for its resistance to mechanical stress and decay. Here we show that this protein fraction contains a set of structural proteins (K6a, K6b, K6c, K16 and K17) that belong to the keratin family and are present specifically in the skin of the palms and soles, as well as in nails. We further show that common genetic mutations that affect the composition of these proteins lead to an increased number of cavities. Rare mutations in these keratins lead to a human disease called pachyonychia congenita (PC) and characterized by severe nail malformations and lesions in the skin of the palms and soles. Analysis of wisdom teeth from one of these patients showed that their enamel exhibited structural defects. These results demonstrate that these keratins are important components of tooth enamel and that common genetic variants in the genes that encode them influence tooth decay risk in the general population.
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影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
4.2
作者：
ROBINSON, C;SHORE, RC;KIRKHAM, J
通讯作者：
KIRKHAM, J
影响因子：
21.3
作者：
Ku, Nam-On;Toivola, Diana M.;Strnad, Pavel;Omary, M. Bishr
通讯作者：
Omary, M. Bishr
影响因子：
15.9
作者：
Duverger, Olivier;Ohara, Takahiro;Morasso, Maria I.
通讯作者：
Morasso, Maria I.
影响因子：
3
作者：
ROBINSON, C;LOWE, NR;WEATHERELL, JA
通讯作者：
WEATHERELL, JA