Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis

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• 作者：Ron Bochner¹ ; ¹² ; Liat Samuelov¹ ; ² ; ¹² ; Ofer Sarig¹ ; ¹² ; Qiaoli Li³ ; Christopher A. Adase² ; Ofer Isakov⁴ ; ⁵ ; Natalia Malchin¹ ; Dan Vodo¹ ; ⁶ ; Ronna Shayevitch⁶ ; Alon Peled¹ ; ⁶ ; Benjamin D. Yu² ; Gilad Fainberg¹ ; Emily Warshauer¹ ; Noam Adir⁷ ; Noam Erez⁸ ; Andrea Gat⁹ ; Yehonatan Gottlieb¹⁰ ; Tova Rogers¹ ; Mor Pavlovsky¹ ; Ilan Goldberg¹ ; Noam Shomron⁴ ; ⁵ ; Aileen Sandilands¹¹ ; Linda E. Campbell¹¹ ; Stephanie MacCallum¹¹ ; W. H. Irwin McLean¹¹ ; Gil Ast⁶ ; Richard L. Gallo² ; Jouni Uitto³ ; Eli Sprecher¹ ; ⁶ ; ^{elisp@tlvmc.gov.il}
• 关键词：ARCI ; autosomal recessive congenital ichthyose ; PCR-RFLP ; PCR-restriction fragment length polymorphism ; siRNA ; small interfering RNA
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：137
• 期：2
• 页码：385-393
• 全文大小：2503 K
• 卷排序：137

文摘

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. G1900Mfs*16), 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.Val364Lysfs*11). 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.