Kato M, etal., J Invest Dermatol. 2015 May;135(5):1253-60. doi: 10.1038/jid.2015.12. Epub 2015 Jan 23.
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.
Monilethrix is a rare condition characterized by a hair shaft anomaly known as beaded hair. It can show either an autosomal dominant or an autosomal recessive inheritance pattern. The autosomal dominant form of monilethrix is caused by mutations in the basic hair keratin genes KRT81, KRT83 or KRT86,
while the autosomal recessive form results from mutations in the desmoglein 4 (DSG4) gene. We define the molecular basis of monilethrix in a Japanese patient who has had sparse and fragile scalp hairs since birth. We performed mutation analysis of candidate genes. In addition, we performed co-immunoprecipitation assays and immunofluorescence studies in cultured cells to investigate the functional consequences caused by a mutation. Mutation analysis resulted in the identification of novel compound heterozygous mutations, c.624delG (p.M208IfsX4) and c.2468G>A (p.W823X), in the DSG4 gene of the patient. Furthermore, we show that the mutant DSG4 protein with the mutation p.W823X severely affects the affinity to plakoglobin protein, which may contribute to disruption of desmosomes in the patient's hair shaft. Our results further underscore the crucial role of the DSG4 gene in differentiation of the hair shaft in humans.
Wang JM, etal., Int J Dermatol. 2015 Oct;54(10):1163-8. doi: 10.1111/ijd.12889. Epub 2015 Jul 14.
BACKGROUND: Localized autosomal recessive hypotrichosis (LAH) is an inherited rare disease caused by DSG4 mutations, characterized by short, sparse, brittle hair affecting restricted areas such as the scalp, trunk, and extremities. To date, DSG4
ght:700;'>DSG4 mutations have been reported in 14 pedigrees of LAH overlapping with monilethrix. METHODS: To clarify the etiology of hair defects for a 2-year-old Chinese girl, peripheral blood, skin, and hair samples were collected, and skin immunohistochemistry, electron microscopy (scanning and transmission types), Vivascope confocal microscopy, and DSG4 sequencing were investigated. RESULTS: The patient presented sparse hairs of various length and follicular hyperkeratotic papules. Eyebrows and lashes were also involved (broke or shed). The biopsy specimen revealed curled ingrown hair shafts within the hair follicle and keratin-filled hair follicles. Scanning electron microscopy revealed hair cuticle loosely and irregularly arranged, as well as a marked warping, curling, cracking, and detachment of hair cuticle. Transmission electron microscopy indicated notable dysadhesion between cells of the outer root sheath. A homozygous mutation A1103G in exon 8 of DSG4 was identified in the patient, resulting in the substitution of an aspartic acid by glycine (D323G) and reduced DSG4 expression in the affected scalp epidermis. CONCLUSIONS: The homozygous A1103G mutation in DSG4 was responsible for the disease development.
