Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis
Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis
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DOI：
10.1001/jamadermatol.2019.0016
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发表时间：
2019-05-01
期刊：
影响因子：
10.9
通讯作者：
Choate, Keith A.
中科院分区：
文献类型：
--
作者：
Atzmony, Lihi;Khan, Habib M.;Choate, Keith A.
重要性 线性汗孔角化症的特征是角化丘疹和斑块的线性和轮状结构，组织学检查中存在冠突片。由于线性汗孔角化症表现在代表角质形成细胞前体的背腹侧迁移模式的 Blaschko 系中，因此有人认为合子后体细胞突变是该疾病的基础。然而，迄今为止，还没有遗传证据支持这一假设。 目的 识别与线性汗孔角化症相关的基因突变。 设计、设置和参与者 对来自 3 个学术医疗中心的 3 名临床和组织学诊断为线性汗孔角化症的参与者的受影响皮肤和血液/唾液样本进行配对全外显子组测序。 干预或暴露 对从线性汗孔角化病中分离出的配对血液/唾液和受影响组织样本进行全外显子组测序主要结果和测量线性汗孔角化症参与者的种系和体细胞基因组特征。结果 3 名参与者中，2 名是男性。参与者年龄从5岁到20岁不等。我们在所有病例中都在受影响的组织中发现了新的种系突变和新的体细胞突变的组合。一名参与者具有种系杂合 PMVK c.329G>A 突变和仅限于病变皮肤的体细胞复制中性杂合性丢失，而另一名参与者则具有种系杂合 PMVK c.79G>T 突变和病变皮肤中的额外 PMVK c.379C>T 突变。在第三位参与者中，MVD 中存在种系剪接位点突变 (c.70 + 5G>A) 和 MVD 中的体细胞缺失，导致病变皮肤内移码和过早密码子终止 (c.811_815del, p.F271Afs*33 移码)。 结论和相关性 我们的研究结果表明，线性汗孔角化症与第二次打击的存在相关编码甲羟戊酸生物合成途径中的酶的基因的合子突变，并提供了进一步的证据，证明甲羟戊酸途径可能是汗孔角化症治疗干预的潜在目标。
IMPORTANCE Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date.OBJECTIVE To identify genetic mutations associated with linear porokeratosis.DESIGN, SETTING, AND PARTICIPANTS Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis.INTERVENTIONS OR EXPOSURES Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions.MAIN OUTCOMES AND MEASURES Germline and somatic genomic characteristics of participants with linear porokeratosis.RESULTS Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift).CONCLUSIONS AND RELEVANCE Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.