Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans

Abstract

Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD. Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. Thus, our analysis indicates that loss of GPNMB, which has been implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation, underlies autosomal-recessive ACD and provides insights into the etiology of amyloidosis and pigment dyschromia.

Silvery hair with dyschromatosis: Griscelli syndrome type 3 or familial gigantic melanocytosis

“…The various differential diagnoses for FGM enlisted in literature are both hereditary disorders including dyschromatosis universalis hereditaria (DUH), dyschromatosis symmetrica hereditaria (DSH), reticulate acropigmentation of Kitamura, Fanconi anemia, dyskeratosis congenita, Dowling Degos disease, and acquired disorders such as arsenical pigmentation, antimalarial‐induced hyperpigmentation, lichen planus pigmentosus, and biliary cirrhosis . Although not mentioned in previous reports, we would like to add amyloidosis cutis dyschromica (ACD), to this list (Table ). Although none shows slivery hairs, the closest differentials in terms of dyschromatosis with absence of other mucocutaneous and/or systemic abnormalities, are DUH, DSH, and ACD (Table ).…”

Molecular basis and inheritance patterns of amyloidosis cutis dyschromica

“…The mutation p.Arg189* is a recurrent pathogenic mutation previously identified in Taiwanese individuals with ACD, while p.Cys413Arg (minor allele frequency of 0.0001631 in East Asian populations) appears to be a new missense mutation, although a different pathogenic amino acid substitution in this residue (p.Cys413Ser) has been found in a Filipino family with ACD …”

“…Regarding the pathobiology of ACD, in vitro knockdown of GPNMB in melanocytes has been shown to induce apoptosis in keratinocytes, although the precise disease mechanisms in vivo still require further elucidation. To date, 12 GPNMB mutations have been identified in ACD (Table ) . Most mutations are nonsense or frameshift mutations with only two documented missense mutations, p.Cys413Arg and p.Cys413Ser, located within the kringle‐like domain of GPNMB , suggesting that this region may be critical for protein structure and function.…”

Three novel mutations in GPNMB in two pedigrees with amyloidosis cutis dyschromica

“…Yang et al . have reported mutations in the GPNMB gene in associated with ACD . Genomic DNA samples were extracted from the peripheral blood of our probands and their family members after informed consent.…”

“…It is highly expressed in melanocytes, is partially localized in melanosomes, lysosomes and early endosomes . GPNMB was found to have critical roles in melanosome formation, autophagy/phagocytosis, clearance of apoptotic cell debris and negative regulation of inflammation, which are associated with ACD . However, the mechanism by which loss‐of‐function GPNMB affects the metabolic pathway and induces the pigment dyschromia and amyloidosis in ACD remains unclear.…”