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.

The Significance of Scalp Involvement in Pemphigus: A Literature Review

“…Some authors suggest that desmoglein 4 may play a role as an additional autoantigen in pemphigus vulgaris [ 9 ]. Mutations in Dsg4 gene are responsible for localized autosomal recessive hypotrichosis [ 11 ], monilethrix [ 12 ], and in some cases an overlap of both [ 13 ]. Schaffer et al reported three cases of localized autosomal recessive hypotrichosis and monilethrix in combination with scalp erosions presenting mutations in the gene for desmoglein 4 [ 14 ].…”

In-frame Val216-Ser217 deletion of KIT in mild piebaldism causes aberrant secretion and SCF response

“…For the immunoprecipitation analyses, the cells were lysed in 1% NP-40/Tris-buffered saline (TBS) supplemented with protease inhibitor cocktail (Roche) and incubated with anti-FLAG M2 affinity gel (Sigma, St Louis, MO, USA) for overnight at 4 C. The agarose beads were washed with lysis buffer five times. The cell lysates, culture media and immunoprecipitate were separated on 7.5% SDS gels (Bio-Rad, Hercules, CA, USA), and immunoblotting was performed as previously described [17].…”

Value of dermoscopy for the diagnosis of monilethrix

“…Four genes are associated with monilethrix and are responsible for autosomal dominant transmission of the disease [1,2]. An autosomal recessive form has also been described and is caused by mutations of gene DSG4 coding for desmoglein 4 [3]. The diagnosis of monilethrix was more difficult to establish in our patient owing to the absence of any familial cases.…”