Heterogeneity in the properties of mutant secreted lymphocyte antigen 6/urokinase receptor-related protein 1 (SLURP1) in Mal de Meleda

Funding sources: This work was supported by P01 HL090553 (S.G.Y.) and a Leducq Transatlantic Network grant (12CVD04). Conflicts of interest: none declared. Dear Editor, Genetic defects in secreted lymphocyte antigen 6 (Ly6)/urokinase receptor (uPAR)‐related protein 1 (SLURP1), a Ly6‐like protein, cause mal de Meleda, a palmoplantar keratoderma. The hallmark of Ly6 proteins is an 80‐amino acid domain containing 10 cysteines, all arranged in a characteristic spacing pattern and all disulfide‐bonded, creating a three‐fingered structural motif (Fig. 1). This sequence motif was initially found in cobra and viper toxins, but was later identified in about 25 mammalian proteins. Most mammalian Ly6 proteins are tethered to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor [e.g. uPAR, CD59, GPI‐anchored high‐density lipoprotein binding protein 1 (GPIHBP1)], but several, including SLURP1, are secreted proteins. SLURP1 is produced in keratinocytes but it diffuses away and can be detected in sweat and urine.1 Many of the SLURP1 mutations in patients with mal de Meleda are missense. To date, no one has compared the properties of mutant SLURP1 proteins. We chose to investigate the properties of mutant SLURP1 proteins as a first step in a longer‐term effort to define SLURP1 protein interactions. We embarked on this project in the wake of discoveries on disease‐causing mutations in GPIHBP1, a Ly6 protein that avidly binds lipoprotein lipase (LPL) and transports it to the capillary lumen. Certain GPIHBP1 missense mutations abolish LPL binding, leading to severe hypertriglyceridaemia.2 3 4 5 Mutations involving cysteines in the Ly6 domain of GPIHBP1 promote GPIHBP1 dimerization and multimerization (i.e. the presence of an unpaired cysteine promotes intermolecular disulfide bonds).6 Protein multimerization is highly relevant to disease pathogenesis because multimers are incapable of binding LPL. Mutations of many other GPIHBP1 residues (aside from the cysteines) also impaired disulfide bonding and led to protein dimerization/multimerization.5 6 Mutations in a few residues (e.g. W109) abolished LPL binding without causing protein multimerization; those residues likely play a direct role in LPL binding.6