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Pigmentation is a common skin disorder that can affect quality of life and place a heavy psychological burden on patients, depending on the degree and location. Pigmented skin can be subdivided into epidermal, dermal, mixed epidermodermal, mucosal and nail pigmentation disorders.1–3 Skin hyperpigmentation can be inherited or acquired. However, inherited hyperpigmented skin disorders comprise a group of entities with considerable clinical and genetic heterogeneity, making their genetic basis difficult to elucidate.

In this issue of the BJD, Jiang et al. reveal loss-of-­function variants in GLMN as a cause of generalized skin hyperpigmentation, regardless of glomuvenous malformation (GVM).4 In five unrelated families with autosomal-­dominant generalized skin hyperpigmentation, the authors used whole-exome and Sanger sequencing to identify the genetic basis of the hyperpigmentation. This approach led to the identification of loss-of-function variants in GLMN, providing novel insights into the pathogenesis of the disease.

Firstly, the identification of GLMN variants as a cause of skin hyperpigmentation expands our understanding of its genetic basis. GLMN encodes the protein glomulin, which acts as a regulatory component of cullin-RING ligases by directly binding to the RING domain of RBX1 to inhibit its E3 ubiquitin ligase activity.5,6 Previous studies have shown that heterozygous loss-of-function mutations in GLMN are the cause of GVM, a skin venous malformation disorder characterized by smooth muscle-like glomus cells surrounding dilated vascular lumens,7 while the study by Jiang et al. suggests a broader role, beyond vascular pathology.4

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