An Autosomal Recessive Mutation of DSG4 Causes Monilethrix through the ER Stress Response Madoka Kato, Akira Shimizu, Yoko Yokoyama, Kyoichi Kaira, Yutaka.

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An Autosomal Recessive Mutation of DSG4 Causes Monilethrix through the ER Stress Response Madoka Kato, Akira Shimizu, Yoko Yokoyama, Kyoichi Kaira, Yutaka Shimomura, Akemi Ishida-Yamamoto, Kiyoko Kamei, Fuminori Tokunaga, Osamu Ishikawa Journal of Investigative Dermatology Volume 135, Issue 5, Pages 1253-1260 (May 2015) DOI: 10.1038/jid.2015.12 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Clinical appearance of the patient. (a) The pedigree of the patient’s family. The patient’s mother was a carrier and her sister was normal. (b) Sparse hair and follicular papules on the scalp. (c) Dermoscopic examination revealed some bent and buried hair in the stratum corneum. (d) A typical moniliform hair on the patient’s scalp, observed by dermoscopy. (e) Periodic nodes and internodes were seen in the plucked moniliform hair by means of light microscopy. (f) Hematoxylin–eosin stain of a moniliform hair in the lower hair follicles. NT, not tested. Bar = 100 μm. Journal of Investigative Dermatology 2015 135, 1253-1260DOI: (10.1038/jid.2015.12) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Transmission electron microscopy (TEM) analysis of a moniliform hair and an anagen hair of the patient. (a) Semithin section of a moniliform hair. (b) Dotted green lines: cuticle cells. (c, d) Higher magnifications of the bottom (c) and top (d) rectangles in (b). (e, f) The lower portion of the hair shaft. (f) Higher magnification of (e). (g) Semithin sections of the anagen hair. (h, i) TEM of the cortex (h) and cuticle (i). (j, k) TEM of cuticle cells in the lower hair follicle. Red arrows: desmosomes. (k) Higher magnification of (j). Co, cortex; Cu, cuticle; Hu, Huxley layer; H, Henle layer; Icu, inner root sheath cuticle. Bars = (a, g) 50 μm, (b, e) 5 μm, (h, i) 2 μm, and (c, d, f, j, k) 1 μm. Journal of Investigative Dermatology 2015 135, 1253-1260DOI: (10.1038/jid.2015.12) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Identification of mutant DSG4. (a) Identification of the DSG4 mutation. Arrow: the deleted G. (b) Domain organization of Wt and mutant DSG4. Arrow: the mutation site; red box: the aberrant region of the mutant DSG4. (c) Sequence of the mutant DSG4. Red: the aberrant sequence; underlined: the peptide sequence for the mutant DSG4–specific antibody. (d–g) Immunofluorescence of the hair cortex with anti-DSG4 (green) and anti-trichohyalin (red) antibodies (d, e) or the mutant DSG4–specific antibody (f, g). (d, f): Patient. (e, g): Normal. Bars = (d–g) 100 μm. (h) Immunoblotting to detect aberrant DSG4 was performed using the described antibodies. DSG, desmoglein; EA, extracellular anchoring; EC, extracellular; IA, intracellular anchor; ICS, intracellular cadherin-typical segment; LD, linker domain; RUD, repeat unit domain; TD, terminal domain; and TM, transmembrane. Journal of Investigative Dermatology 2015 135, 1253-1260DOI: (10.1038/jid.2015.12) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 The mutant DSG4 failed to bind PKG. Expression plasmids, including pcDNA3.1-DSG4-Wt-HA, pcDNA3.1-DSG4-mutant (mut)-HA, and pcDNA3.1-FLAG-PKG, were transiently transfected into HEK293T cells. Cell lysates were prepared, immunoprecipitated with the indicated antibodies, and electrophoresed. Immunoblottings were performed with the indicated antibodies. DSG, desmoglein; IP, immunoprecipitation. Journal of Investigative Dermatology 2015 135, 1253-1260DOI: (10.1038/jid.2015.12) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 The mutant DSG4 is localized in the ER. Immunofluorescent staining of DSG4 and the ER-resident chaperone, calnexin. DSG4-mut-HA and DSG4-Wt-HA were expressed in HEK293T cells, and DSG4 (a, b) and endogenous calnexin (c, d) were stained. (e, f) DAPI stain and merged image. Bars = (a–f) 5 μm. (g) N-glycosylation of DSG4-Wt and DSG4-mut. The HEK293T cell lysates, from cells transiently expressing DSG4-Wt-HA or DSG4-mut-HA, were treated with Endo H or PNGase F. After SDS-PAGE, immunoblotting was performed with an anti-HA antibody. DSG, desmoglein; Endo H, endoglycosidase H; ER, endoplasmic reticulum. Journal of Investigative Dermatology 2015 135, 1253-1260DOI: (10.1038/jid.2015.12) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 The mutant DSG4 tethered in the ER induces UPR and ERAD. Immunohistochemistry of the patient’s epidermis, using an anti-GRP78/BiP antibody. In comparison with the normal epidermis (b), GRP78/BiP was slightly expressed in the patient’s granular layer of the epidermis (a). Bars = (a, b) 100 μm. (c) HEK293T cells, transfected with pcDNA3.1-DSG4-Wt-HA or pcDNA3.1-DSG4-mut-HA, were treated with 10 μM MG132 or DMSO for 4 hours. The DSG4 proteins were detected by an anti-HA antibody. As an internal control, β-actin was also detected. DSG, desmoglein; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum–associated degradation; UPR, unfolded protein response. Journal of Investigative Dermatology 2015 135, 1253-1260DOI: (10.1038/jid.2015.12) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions