Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Dermatology, University of California, San Diego, California, USA.
J Invest Dermatol. 2017 Feb;137(2):385-393. doi: 10.1016/j.jid.2016.07.043. Epub 2016 Oct 18.
Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.
先天性红皮病是一种罕见且通常危及生命的疾病，其已被证实由编码表皮分化程序重要成分的几个基因突变引起。我们通过全外显子组测序，在一名患有先天性剥脱性红皮病、少毛症、严重指甲营养不良和生长不良的儿童中，发现 ABCA12 基因（c.2956C>T，p.R986W；c.5778+2T>C，p.G1900Mfs16）的两个杂合突变，该基因与两种鱼鳞病相关，常染色体隐性先天性鱼鳞病和丑角鱼鳞病。由于患者表现出非典型表型，包括严重的毛发和指甲表现，我们仔细检查外显子组测序数据中与角质化过程相关的基因中是否存在其他潜在的有害遗传变异。在 CAPN12 基因中发现了两个突变，该基因编码钙蛋白酶蛋白酶的一个成员：一个来自父亲的错义突变（c.1511C>A；p.P504Q）和一个由于基因 9 号外显子中隐蔽剪接位点的激活导致的来自母亲的缺失（c.1090_1129del；p.Val364Lysfs11）。钙蛋白酶 12 蛋白在正常皮肤的表皮和毛囊中均有表达，但在患者皮肤中的表达显著降低。斑马鱼中 capn12 表达的下调与异常表皮形态发生有关。在三维人体皮肤模型中，CAPN12 的小干扰 RNA 敲低与棘皮症、表皮结构紊乱以及几个分化标志物（包括丝聚蛋白）的下调有关。因此，患者皮肤中的丝聚蛋白表达几乎缺失。通过体外活体成像，与对照相比，K14-H2B GFP 小鼠皮肤中小干扰 RNA 敲低钙蛋白酶 12 可导致显著的毛囊休止期转化。总之，我们的结果表明钙蛋白酶 12 在表皮发生和正常毛囊周期中发挥重要作用，其缺失可能会加重 ABCA12 突变的临床表现。
