Mutations in GPNMB associated with Amyloid cutis dyschromica alter intracellular trafficking and processing of GPNMB

Amyloid cutis dyschromica (ACD) is a rare skin condition characterized by focal areas of hyperpigmentation with hypopigmented macules and distinct regions of amyloid deposition. Until recently, the genetic cause of ACD remained unknown. Several studies have since named GPNMB truncation mutations as causal, with protein loss-of-function underlying ACD pathogenesis. GPNMB missense mutations have also been observed in patients, but these are less well characterized; especially on a cellular level. Here, we observed that GPNMB missense mutations implicated in familial ACD show distinct cellular phenotypes that result in impaired protein maturation and processing from the endoplasmic reticulum (ER) to the trans -Golgi network (TGN), prompting failed trafficking to lysosomes. These missense mutations also show failed secretion of the extracellular fragment of GPNMB, a well-characterized property of the protein. Overall, this work highlights previously undescribed cellular characteristics of GPNMB missense mutations implicated in ACD and helps to better inform the clinically observed phenotypes, as well as underscore GPNMB’s role at melanosomes. ### Competing Interest Statement The authors have declared no competing interest. * (ACD) : Amyloid cutis dyschromica (PLCA) : Primary localized cutaneous amyloidosis (GPNMB) : Glycoprotein nonmetastatic protein B (NIPAL2) : NIPA like domain containing 2 (RGD) : Arginyl-glycyl-aspartic acid (PKD) : Polycystic kidney disease (KLD) : Kringle-like domain (TFEB) : Transcription factor EB (LROs) : Lysosome related organelles (MITF) : Microphthalmia-associated transcription factor (TM) : Transmembrane (ADAM10) : A disintegrin and metalloproteinase domain-containing protein 10 (Di-L) : Di-leucine (EGFP) : Enhanced green fluorescent protein (FCS) : Fetal calf serum (PBS) : Phosphate-buffered saline (LLOMe) : L-leucyl-L-leucine methyl ester (PFA) : Paraformaldehyde (DAPI) : 4′,6-diamidino-2-phenylindole (BSA) : Bovine serum albumin (ER) : Endoplasmic reticulum (TGN) : trans-Golgi network