Mutation p.Leu128Pro in the 1A domain of K16 causes pachyonychia congenita with focal palmoplantar keratoderma in a Chinese family
Mutation p.Leu128Pro in the 1A domain of K16 causes pachyonychia congenita with focal palmoplantar keratoderma in a Chinese family
复制标题
K16 1A 结构域 p.Leu128Pro 突变导致中国家庭先天性厚甲症伴局灶性掌跖角化症
DOI：
10.1007/s00431-013-2236-8
复制
发表时间：
2014-06-01
影响因子：
3.6
通讯作者：
Liao, Qiong
中科院分区：
文献类型：
--
作者：
Dai, Limeng;Wu, Jun;Liao, Qiong
先天性厚甲症 (PC) 是一种罕见的常染色体显性遗传疾病，以肥厚性指甲营养不良为特征，主要分为两种临床亚型：PC-1 和 PC-2。 PC-1 与 KRT6A 或 KRT16 基因突变相关，而 PC-2 与 KRT6B 或 KRT17 突变相关。血液样本采集自一个新的中国PC-1家族的三代人，包括三名PC患者和五名未受影响的家庭成员。在 K16 结构域 1A 的高度保守的螺旋基序中鉴定出新的错义突变 p.Leu128Pro (c.383T>C)。疾病单倍型携带突变并与感染状态共分离。 PolyPhen2 和 SIFTS 分析将替代品评为可能具有破坏性；瑞士模型分析表明，突变蛋白的结构含有不正常的α-螺旋。培养细胞中突变蛋白的过度表达导致细胞形态异常。结论：更广泛的 KRT16 突变表明密码子 125、127 和 132 的变化是 PC-1 最常见的原因，而密码子 127 或 128 处的脯氨酸取代突变可能会产生更严重的疾病。这项研究扩展了 KRT16 突变谱，并增加了有关 PC 临床和遗传多样性的新信息。
Pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by hypertrophic nail dystrophy, is classified into two main clinical subtypes: PC-1 and PC-2. PC-1 is associated with mutations in the KRT6A or KRT16 genes, whereas PC-2 is linked to KRT6B or KRT17 mutations. Blood samples were collected from three generations of a new Chinese PC-1 family, including three PC patients and five unaffected family members. A novel missense mutation p.Leu128Pro (c.383T>C) was identified in a highly conserved helix motif in domain 1A of K16. The disease haplotype carried the mutation and cosegregated with the affection status. PolyPhen2 and SIFTS analysis rated the substitution as probably damaging; Swiss-Model analysis indicated that the structure of the mutant protein contained an unnormal α-helix. Overexpression of mutant protein in cultured cells led to abnormal cell morphology.Conclusion:The wider spectrum of KRT16 mutations suggests that changes in codons 125, 127, and 132 are most commonly responsible for PC-1 and that proline substitution mutations at codons 127 or 128 may produce more severe disease. This study extends the KRT16 mutation spectrum and adds new information on the clinical and genetic diversity of PC.