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

Ron Bochner, Liat Samuelov, Ofer Sarig, Qiaoli Li, Christopher A. Adase, Ofer Isakov, Natalia Malchin, Dan Vodo, Ronna Shayevitch, Alon Peled, Benjamin D. Yu, Gilad Fainberg, Emily Warshauer, Noam Adir, Noam Erez, Andrea Gat, Yehonatan Gottlieb, Tova Rogers, Mor Pavlovsky, Ilan GoldbergNoam Shomron, Aileen Sandilands, Linda E. Campbell, Stephanie MacCallum, W. H.Irwin McLean, Gil Ast, Richard L. Gallo, Jouni Uitto, Eli Sprecher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish
Pages (from-to)385-393
Number of pages9
JournalJournal of Investigative Dermatology
Issue number2
StatePublished - 1 Feb 2017


FundersFunder number
National Institute of Arthritis and Musculoskeletal and Skin DiseasesT32AR062496
National Institute of Arthritis and Musculoskeletal and Skin Diseases


    Dive into the research topics of 'Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis'. Together they form a unique fingerprint.

    Cite this