title: Calpain 12 Function Revealed through the Study of an Atypical Case of Autosomal Recessive Congenital Ichthyosis.
abstract: 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.
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Ron
authors: R
authors: Bochner
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Dermatology, University of California, San Diego, California, USA.
authors: Liat
authors: L
authors: Samuelov
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Ofer
authors: O
authors: Sarig
authors: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors: Qiaoli
authors: Q
authors: Li
authors: Department of Dermatology, University of California, San Diego, California, USA.
authors: Christopher A
authors: CA
authors: Adase
authors: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Variantyx Ltd, Ashland, USA.
authors: Ofer
authors: O
authors: Isakov
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Natalia
authors: N
authors: Malchin
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Dan
authors: D
authors: Vodo
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Ronna
authors: R
authors: Shayevitch
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Alon
authors: A
authors: Peled
authors: Department of Dermatology, University of California, San Diego, California, USA.
authors: Benjamin D
authors: BD
authors: Yu
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Gilad
authors: G
authors: Fainberg
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Emily
authors: E
authors: Warshauer
authors: Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Noam
authors: N
authors: Adir
authors: The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Noam
authors: N
authors: Erez
authors: Department of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Andrea
authors: A
authors: Gat
authors: Research Laboratory for Pediatric Hemato-Oncology, Dana Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Yehonatan
authors: Y
authors: Gottlieb
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Tova
authors: T
authors: Rogers
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Mor
authors: M
authors: Pavlovsky
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors: Ilan
authors: I
authors: Goldberg
authors: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Variantyx Ltd, Ashland, USA.
authors: Noam
authors: N
authors: Shomron
authors: Centre for Dermatology and Genetic Medicine, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
authors: Aileen
authors: A
authors: Sandilands
authors: Centre for Dermatology and Genetic Medicine, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
authors: Linda E
authors: LE
authors: Campbell
authors: Centre for Dermatology and Genetic Medicine, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
authors: Stephanie
authors: S
authors: MacCallum
authors: Centre for Dermatology and Genetic Medicine, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK.
authors: W H Irwin
authors: WHI
authors: McLean
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Gil
authors: G
authors: Ast
authors: Department of Dermatology, University of California, San Diego, California, USA.
authors: Richard L
authors: RL
authors: Gallo
authors: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors: Jouni
authors: J
authors: Uitto
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: elisp@tlvmc.gov.il.
authors: Eli
authors: E
authors: Sprecher
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002154:Calpain / Q000235:genetics / Q000502:physiology*; D002648:Child; D000091344:Filaggrin Proteins; D018859:Hair Follicle / Q000502:physiology; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000473:pathology; D007381:Intermediate Filament Proteins / Q000032:analysis; D008297:Male; D051379:Mice; D009154:Mutation; D015027:Zebrafish
chemical_list: C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; C418723:CAPN12 protein, human; D002154:Calpain