Amyloidosis cutis dyschromica (ACD) is an autosomal recessive disorder characterized by prepubertal onset of reticular hyperpigmentation with hypopigmented spots, and amyloid deposition in the upper dermis. Recently, bi-allelic mutations in GPNMB (encoding a glycoprotein involved in melanosome maturation) have been described. By undertaking whole-exome sequencing in three affected individuals with ACD from an extended consanguineous pedigree, we identified a single previously unreported splicing variant (c.700+5G>T) in GPNMB. We also sequenced GPNMB exons and flanking intronic regions in two additional ACD individuals and identified a further unreported homozygous GPNMB variant (c.1238G>C; p.Cys413Ser) and compound heterozygosity for previously reported mutations (c.565C>T; p.Arg189* and c.1056del; p.Pro353Leufs*20). Sanger-sequencing of the four variants in all available family members showed a semi-dominant pattern of inheritance in the three pedigrees, with heterozygotes displaying milder clinical features of skin dyschromia. Moreover, qPCR in RNA from whole skin biopsies in three individuals with different genotypes of the c.700+5G>T GPNMB mutation, showed approximately 35% reduction in GPNMB expression in a heterozygous affected member, and almost no expression in a homozygous individual (in both dark and light skin) when compared to a wild-type unaffected family member. Immunofluorescence analysis showed markedly reduced GPNMB in homozygote skin, patchy reduction in melanocyte numbers and basal keratinocyte melanin, as well as positive amyloid labelling in the papillary dermis. In summary, these data expand the mode of inheritance in ACD, highlighting semi-dominant inheritance rather than just autosomal recessive transmission, and identify two new mutations in GPNMB.

Exome sequencing identifies semi-dominant GPNMB mutations in amyloidosis cutis dyschromica