A Large Mutational Study in Pachyonychia Congenita
A Large Mutational Study in Pachyonychia Congenita
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DOI：
10.1038/jid.2011.20
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发表时间：
2011-05-01
影响因子：
6.5
通讯作者：
Smith, Frances J. D.
中科院分区：
文献类型：
--
作者：
Wilson, Neil J.;Leachman, Sancy A.;Smith, Frances J. D.
先天性厚甲症是一种罕见的常染色体显性遗传性皮肤病，主要表现为指甲营养不良和疼痛性掌跖角化病。其他临床特征包括口腔白斑角化病、毛囊角化病和囊肿（脂肪囊肿和毛囊皮脂腺囊肿）。PC是由于四种角蛋白基因之一的杂合突变，即KRT 6A，KRT 6 B，KRT 16或KRT 17。在这里，我们报告了90个新的PC家族的遗传分析，其中我们确定了KRT 6A，KRT 6 B，KRT 16或KRT 17的突变，从而证实了他们的临床诊断。共有21个以前未报道的突变和22个已知的突变被发现。大约一半的激酶有KRT 6A突变（52%），28%的KRT 16突变，17%的KRT 17突变，3%的家庭有KRT 6 B突变。大多数突变是杂合错义或小的框内插入/缺失突变，发生在角蛋白多肽的螺旋边界基序区域之一内。更不寻常的突变包括杂合剪接位点突变、无义突变和1-bp插入突变，导致移码和提前终止密码子。这项研究，连同以前报道的突变，确定突变热点密码子，可能是有用的PC的个性化药物的发展。
Pachyonychia congenita (PC) is a rare autosomal dominant skin disorder characterized predominantly by nail dystrophy and painful palmoplantar keratoderma. Additional clinical features include oral leukokeratosis, follicular keratosis, and cysts (steatocysts and pilosebaceous cysts). PC is due to heterozygous mutations in one of four keratin genes, namely, KRT6A, KRT6B, KRT16, or KRT17. Here, we report genetic analysis of 90 new families with PC in which we identified mutations in KRT6A, KRT6B, KRT16, or KRT17, thereby confirming their clinical diagnosis. A total of 21 previously unreported and 22 known mutations were found. Approximately half of the kindreds had mutations in KRT6A (52%), 28% had mutations in KRT16, 17% in KRT17, and 3% of families had mutations in KRT6B. Most of the mutations were heterozygous missense or small in-frame insertion/deletion mutations occurring within one of the helix boundary motif regions of the keratin polypeptide. More unusual mutations included heterozygous splice site mutations, nonsense mutations, and a 1-bp insertion mutation, leading to a frameshift and premature termination codon. This study, together with previously reported mutations, identifies mutation hotspot codons that may be useful in the development of personalized medicine for PC.