Nonsense Mutations in AAGAB Cause Punctate Palmoplantar Keratoderma Type Buschke-Fischer-Brauer
Nonsense Mutations in AAGAB Cause Punctate Palmoplantar Keratoderma Type Buschke-Fischer-Brauer
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DOI：
10.1016/j.ajhg.2012.08.024
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发表时间：
2012-10-05
影响因子：
9.8
通讯作者：
Strom, Tim M.
中科院分区：
文献类型：
--
作者：
Giehl, Kathrin A.;Eckstein, Gertrud N.;Strom, Tim M.
点状掌跖角化病是一种罕见的常染色体显性遗传性皮肤病，以分布于手掌和脚掌的多个角化过度斑块为特征。迄今为止，已报道了染色体区域15 q22 - 15 q24和8q24.13-8q24.21中的两个不同位点。然而，致病性突变尚未确定。为了阐明Buschke-Fischer-Brauer（PPKP 1）型PPKP的遗传病因，我们对来自3个家族的5名患病个体进行了外显子组测序，并在所有患病个体的染色体区域15 q22.33-q23中鉴定出两个杂合无义突变--c.370C>T（p.Arg124（星星））和c.481C>T（p.Arg161（星星））。使用免疫印迹分析，我们表明，这两个突变导致翻译和截短的蛋白质产物的提前终止。对受影响个体的mRNA分析显示，疾病等位基因要么检测不到，要么只能在低水平下检测到。为了评估皮肤突变的后果，我们进行了免疫荧光分析。值得注意的是，受影响个体的角质形成细胞中的颗粒染色的量在细胞质中较低，但在细胞核周围高于对照个体的角质形成细胞。AAGAB编码α-和γ-适应素结合蛋白p34，并可能作为伴侣在膜运输中发挥作用。突变的鉴定，沿着其他研究的结果，定义了PPKP 1的遗传基础，并提供了AAGAB在皮肤完整性中起重要作用的证据。
Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations-c.370C>T (p.Arg124(star)) and c.481C>T (p.Arg161(star))-in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity.