Uncovering the etiology of amyloidosis cutis dyschromica in human A team led by Dr. Jer-Yuarn Wu and Dr. Yuan-Tsong Chen at the Institute of Biomedical Sciences in Academia Sinica discovered for the first time that loss of GPNMB causes autosomal-recessive amyloidosis cutis dyschromica. This research was published on February 1, 2018 in the American Journal of Human Genetics.
Uncovering the etiology of autosomal-recessive amyloidosis cutis dyschromica in human: loss of GPNMB
Amyloidosis cutis dyschromica (ACD) is predominantly observed in East and Southeast Asian individuals; however, the inheritance mode and genetic cause has not been elucidated. A team led by Dr. Jer-Yuarn Wu and Dr. Yuan-Tsong Chen at the Institute of Biomedical Sciences in Academia Sinica discovered for the first time that loss of GPNMB causes autosomal-recessive ACD. This research was published on February 1, 2018 in the American Journal of Human Genetics.
The clinical features of ACD include generalized hyperpigmentation mottled
with small hypopigmented macules or patches distributed over the trunks and limbs in a symmetrical pattern; small foci of amyloid deposition in the papillary dermis; onset before puberty; and mild or no pruritus. A previous reported review suggest that ACD may exhibit autosomal dominance inherited with incomplete penetrance. This study examined nine ACD-affected individuals in which the mode of inheritance was autosomal recessive and identified biallelic truncating mutations in each individual, including nonsense mutations and frameshift mutations.
Recent studies have discovered that GPNMB is expressed in numerous tissues and cell types. GPNMB was found to have critical roles in melanosome formation, autophagy, phagocytosis, clearance of apoptotic cell debris, and negative regulation of inflammation. Gpnmb mutant mice exhibit iris pigment dispersion as well as pigmentary glaucoma as combining Tryp1 mutations (Tryp1 mutations contribute to the iris stromal atrophy phenotype in mouse pigment glaucoma). However, no mutations in GPNMB and TYRP1 genes have been identified in human pigmentary glaucoma and pigment dispersion syndrome.
This study identified that GPNMB is expressed in all human epidermal cells, with the highest staining observed in melanocytes. GPNMB expression is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions showed hepermelanosis in the epidermis, dropping off of epidermal melanin granules
into the papillary dermis and upper dermis, and melanophages. Amyloid deposits were greatly enriched in the papillary dermis of hyperpigmented lesions compared with that in depigmented macules. Amyloid deposits contain keratin and DNA debris, suggesting that degeneration and death of keratinocytes contribute to the formation of amyloid deposits. Infiltrating immune cells were evident adjacent to and beneath amyloid deposits, in which macrophages were significantly accumulated in hyperpigmented lesions. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. The pigment dyschromia and amyloidosis in ACD caused by GPNMB mutations potentially relate to increased or chronic inflammatory responses, misfolded protein aggregates, reduced clearance of cellular debris and protein aggregates, keratinocyte degeneration, and melanocyte survival. This study expands our understanding to the etiology of amyloidosis and pigment dyschromia in ACD.
The article entitled “Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans” can be found at
The complete list of author is: Chi-Fan Yang, Shuan-Pei Lin, Chien-Ping Chiang, Yu-Hung Wu, Weng Siong H'ng, Chun-Ping Chang, Yuan-Tsong Chen, and Jer-Yuarn Wu
Dr. Jer-Yuarn Wu, Institute of Biomedical Sciences, Academia Sinica
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