title: An autosomal recessive mutation of DSG4 causes monilethrix through the ER stress response.
abstract: Monilethrix is a hair shaft anomaly characterized by beaded hair with periodic changes in hair thickness. Mutations in the desmoglein 4 (DSG4) gene reportedly underlie the autosomal recessive form of the disease. However, the pathogenesis and cellular basis for the DSG4 mutation-induced monilethrix remained largely unknown. We report a Japanese female patient with monilethrix. Observation of her hair shaft by means of transmission electron microscopy showed fewer desmosomes and abnormal keratinization. Genetic analysis revealed a homozygous mutation, c.2119delG (p.Asp707Ilefs*109), in the DSG4 gene, which was predicted to cause a frameshift and premature termination in the intracellular region of the DSG4 protein. The mutation has not been reported previously. In the patient's hair shaft, we detected reduced but partial expression of the mutant DSG4 protein. Cellular analyses demonstrated that the mutant DSG4 lost its affinity to plakoglobin and accumulated in the endoplasmic reticulum (ER). The amounts of mutant DSG4 were increased by proteasome inhibitor treatment, and the expression of an ER chaperone, GRP78/BiP, was elevated in the patient's skin. Collectively, these results suggest that the dysfunctional mutated DSG4, tethered in the ER, undergoes ER-associated degradation, leading to unfolded protein response induction, and thus ER stress may have a role in the pathogenesis of monilethrix.
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan. Electronic address: shimizuakira@gunma-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Kaira
authors.affiliation: Laboratory of Genetic Skin Disease, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
authors.affiliation: Department of Dermatology, Asahikawa Medical University, Hokkaido, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.affiliation: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kamei
authors.affiliation: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tokunaga
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D051182:Desmogleins / Q000235:genetics* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D018859:Hair Follicle / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006360:Heat-Shock Proteins / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D056734:Monilethrix / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: C473409:DSG4 protein, human; D051182:Desmogleins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins